JPH0774145B2 - Emulsion composition containing crystalline drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a drug, a medicine, which comprises an O / W emulsion containing an O / W microemulsion containing a crystalline drug in a supersaturated state. The present invention relates to an O / W type emulsion useful in the field of quasi-drugs or cosmetics. Here, the crystalline drug means a drug insoluble in water and does not include a water-soluble drug.

[Prior Art] Generally, an ointment base, a solution, or an emulsion base has been often used for formulating a crystalline drug insoluble in water.

In particular, when a crystalline drug is mixed in the emulsion, the crystal is made into fine crystals to enhance the transdermal absorbability of the drug, it is clathrated with cyclodextrin, etc., the crystal transition is utilized, and the high water solubility is achieved. In the combination of molecules, a complex has been formed, and a transdermal absorption enhancer such as Azone, oleyl alcohol, medium chain triglyceride, sodium pyrrolidone carboxylic acid has been blended, but transdermal absorption is not yet sufficient, Moreover, the skin irritation and stability are not always satisfactory.

[Problems to be Solved by the Invention] In order to emulsify a crystalline drug, crystals may be finely pulverized and blended to enhance the transdermal absorbability, but in order to further enhance the transdermal absorbability, the drug should be added. It is better to dissolve in oil to make it molecular. Crystalline drugs generally dissolve in relatively polar oils, but are less soluble in nonpolar oils, while highly polar oils have poor emulsion stability.

Further, in order to enhance the release of the drug from the base, it is desirable that the concentration of the drug in the oil phase be saturated solubility or higher, but if it is higher than the saturated solubility, the drug crystals will always precipitate in the base. Will end up.

For liquid drugs and drugs with a low melting point, it is possible to mix drugs up to the saturated solubility relatively easily, but drugs with high crystallinity (melting point of 60 ° C or higher) should be stably mixed in a supersaturated state. I couldn't.

[Means for Solving Problems] In view of the above circumstances, the present inventor has earnestly studied to obtain a crystalline drug-containing emulsion composition excellent in stability, skin safety, transdermal absorbability, and usability. As a result, the O / W microemulsion containing the crystalline drug in supersaturation was prepared in advance,
Furthermore, by adding this microemulsion to another O / W type emulsion, it is possible to obtain an emulsified composition having good transdermal absorbability, good stability, and satisfactory skin irritation and texture. Found and completed the present invention.

That is, the present invention contains a crystalline drug in a supersaturated state.
The present invention provides an O / W type emulsion obtained by adding an O / W type microemulsion to a separately prepared O / W type emulsion.

Hereinafter, the present invention will be described in detail.

The crystalline drug used in the present invention is a water-insoluble drug, for example, indomethacin, mefenamic acid, flufenalic acid, ketoprofen, diclofenac, glycyrrhizinic acid, prednisolone, dexamethasone, betamethasone, dexamethasone acetate, beclomethasone propionate, valeric acid acetic acid. Examples include anti-inflammatory agents such as prednisolone, antifungal agents such as tolnaftate, griseofulvin, clotocumazole, ketoconazole, tricyclate and miconazole, and cardiotonic agents such as ubidecarenone.

In the present invention, the crystalline drug is emulsified into a microemulsion having an average particle size of 0.5 μ or less. The emulsification method is not particularly limited, but it is preferable to emulsify using a hydrophilic surfactant having an HLB of 12 or more.

The surfactant may be a nonionic surfactant, an ionic surfactant or an amphoteric surfactant. Examples of nonionic surfactants include polyoxyalkylene-based, polyglycerin fatty acid ester, tween-based, sugar ester, etc.
As the ionic surfactant, fatty acid soap, alkyl sulfonate, alkyl phosphate, ether phosphate,
Examples include fatty acid salts of basic amino acids, triethanolamine soap, alkyl quaternary ammonium salts, and amphoteric surfactants such as betaine and aminocarboxylic acid salts.

The oil containing the above-mentioned drug in a supersaturated state, which is to be emulsified in water by the above-mentioned surfactant, includes adipic acid, pimelic acid, azelaic acid, sebacic acid, lower dialkyl esters such as phthalic acid, olive oil, soybean oil, rapeseed. Triglycerides such as oils, coconut oil and beef tallow, synthetic oils such as oleyl oleate, decyl oleate, isopropyl myristate and isopropyl palmitate, higher alcohols such as oleyl alcohol and octadecyl alcohol, higher fatty acids such as oleic acid and isostearic acid, or liquid paraffin. Oils such as, squalane and silicone are exemplified. Those that are liquid at room temperature are preferred.

When emulsifying, ultrasonic emulsifier or Mantongaurin,
It is preferable to use a cooperative emulsifying machine such as a microfluidizer, and a microemulsion having a fine particle size can be easily obtained.

In the emulsified composition, in addition to a crystalline drug, a surfactant and an oil component, for example, glycerin, propylene glycol, 1,3
-Adding a polyhydric alcohol such as butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol or mannitol is more preferable in terms of production and stability of the microemulsion.

The surfactants are preferably used alone, but two or more kinds may be used in combination.

As the oil component, any one type or two or more types are appropriately selected and used from the above.

The amounts of the crystalline drug, surfactant and oil are preferably the following values.

That is, 0.05 to 10% by weight of crystalline drug and 0.5 of surfactant.
-20% by weight, oil content 5-70% by weight.

When a polyhydric alcohol is further added, it is preferably 5 to 50% by weight.

The microemulsion thus obtained is blended in a separately prepared O / W type emulsion.

The O / W type emulsion is not particularly limited, but a surfactant that easily has a liquid crystal structure is preferable. Examples of lipophilic surfactants include stearic acid monoglyceride, palmitic acid monoglyceride, behenic acid monoglyceride, batyl alcohol, chimyl alcohol, polyoxyethylene hydrogenated castor oil derivative, sorbitan monostearate, sorbitan monopalmitate, sorbitan monomyristate, etc. It is preferable to use it in combination with a hydrophilic surfactant. Nonionic surfactants and amphoteric surfactants may be used as the hydrophilic surfactant, but fatty acid soap,
Ionic surfactants such as triethanolamine soap and basic amino acid soap are preferred.

As the oil component to be emulsified, any general oil component can be used, but preferably higher alcohols, fatty acids, cholesterols, fatty acid triglycerides, isopropyl myristate, isopropyl palmitate, decyl oleate which are easily hydrated with water and have a liquid crystal structure. , Liquid paraffin, squalane, silicone oil and the like are preferable.

The manufacturing method is arbitrary.

As the surfactant and the oil component, any one kind or two or more kinds are appropriately selected and used from the above.

The amounts of the surfactant and oil are preferably the following values. That is, the surfactant is 0.5 to 20% by weight and the oil content is 5 to 70% by weight.

The emulsion particle size is not particularly limited, but is preferably 1 to 5
is μ.

The above-mentioned O / W microemulsion is added to the O / W emulsion thus obtained.

The amount of the O / W microemulsion blended is 5 to 70% (% by weight) with respect to the amount of the O / W emulsion.

The compounding method is not particularly limited. Preferably 50-70 ° C
It is advisable to add it under stirring at the temperature of 3 and to cool it to room temperature immediately.

The O / W type emulsion containing the O / W type microemulsion thus prepared in the system preferably has a viscosity of 200,000 cps (measured with a Vismetron VH type) or more. More preferably, it is 300,000 cps or more.

As described above, the present invention is an O / W type emulsion obtained by blending an O / W type microemulsion containing a crystalline drug in a supersaturated state in the O / W type emulsion. It is superior to other conventional external preparations for skin in terms of sex and safety to the skin.

If the internal phase ratio of the O / W type microemulsion is increased and the viscosity of the system is increased, an emulsion composition having the same viscosity as the emulsion composition of the present invention can be obtained, but the oil content increases and the usability increases. Is not preferable, the transdermal absorbability of the crystalline drug is not improved, and the crystalline drug is immediately deposited.
The same applies when the outer phase of the O / W type microemulsion is solidified with a mineral thickener such as bentonite or a water-soluble thickener such as polypinyl alcohol.

As in the present invention, the object of the present invention can be achieved for the first time by incorporating an O / W type microemulsion containing a crystalline drug in a supersaturated state into a separately prepared O / W type emulsion.

In the O / W type emulsion according to the present invention, various components generally used in pharmaceuticals and cosmetics, that is, water-soluble drugs, oil-soluble drugs, absorption-promoting, as needed, within a range that does not impair the effects of the present invention. Agent, powder ingredient, thickener, aquatic ingredient,
Preservatives, antioxidants, fragrances, coloring agents and the like can be added. These may be mixed in advance in the O / W type microemulsion or may be mixed in the O / W type emulsion.

〔Example〕

Next, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.
In the following examples, "%" indicates "% by weight" unless otherwise specified. The particle size of the microemulsion was measured with Nicomp Model 270 (manufactured by HIAC ROYCO), and the viscosity was measured with.

Example 1 1 tolnaftate 2.0% 2 diethyl phthalate 13.0 3 olive oil 6.0 4 liquid paraffin 1.0 5 POE (80 mol) hydrogenated castor oil derivative 3.0 6 propylene glycol 10.0 7 glycerin 4.0 15 'purified water qs 8 cetanol 3.0 9 stearic acid 2.0 10 Miglyol 812 1.0% (manufactured by Dynamite Nobel) 11 Glycerin monostearate 3.0 12 Ethylparaben Appropriate amount 13 Potassium hydroxide 0.1 14 Carboxyvinyl polymer 0.05 15 Purified water 51.75 (Production method) After adding component 1 to component 2 and heating and dissolving, After cooling to 40 ° C., ingredients 3 and 4 were sequentially added to this to prepare an oil phase.
Separately, components 5 and 15 'were added to components 6 and 7 and dissolved by heating to prepare an aqueous phase. Next, while adding the oil phase to the aqueous phase, emulsification was carried out for 2 minutes using a homomixer as preliminary emulsification, and further 200 kg / cm ² using a Manton Gaulin homogenizer.
The obtained microemulsion having a particle size of 0.1 μm was obtained by treating 10 times with.

Separately, components 8, 9, 10, 11, and 12 were heated and dissolved at 70 ° C. to prepare an oil phase. On the other hand, component 1513 was added and heated to 70 ° C to prepare an aqueous phase. Add the oil phase to the water phase and emulsify it, then add the previously dissolved ingredient 14 and use a homomixer at 10,000 rpm for 2 minutes to add the previously prepared microemulsion. Then, the mixture was treated with a homomixer at 6,000 rpm for 2 minutes, stirred and cooled to 25 ° C, and the viscosity of tornafate contained in a supersaturated state was 350,000 cp.
An emulsion composition of s was obtained.

Example 2 1 Indomethacin 1.0% 2 Diethyl phthalate 13.0 3 Miglyol 812 6.0 (manufactured by Dynamite Nobel) 4 Liquid paraffin 0.5 5 Decaglycerin monooleate 2.0 6 Glycerin 5.0 7 1,3-Butylene glycol 7.0 16 'Purified water Appropriate amount 8 cetyl Alcohol 4.0 9 Stearic acid 3.0 10 Glycerin monostearate 2.5 11 Isopropyl myristate 4.0 12 Dimethylpolysiloxane 2.0 13 Ethylparaben Appropriate amount 14 Veegum S-6198 0.3% (manufactured by Vanderbilt) 15 Potassium hydroxide 0.15 7'1,3- Butylene glycol 3.0 16 Purified water 49.55 (Production method) Add component 1 to component 2 and heat to dissolve, then add components 3 and 4
Were sequentially added to prepare an oil phase. On the other hand, the component 5 was dissolved in the components 6 and 7 by heating and then the component 16 'was added to prepare an aqueous phase. Next, while treating with a Polytron emulsifier, the oil phase was gradually added to the aqueous phase and treated for 5 minutes to obtain a microemulsion containing the desired indomethacin with a particle size of 0.4μ in a supersaturated state.

Separately, components 8, 9, 10, 11, 12, and 13 were heated and dissolved at 75 ° C. to prepare an oil phase. Meanwhile, add components 14, 15, 7'to component 16
After heating to 75 ° C and dispersing using a 1 / 4HP homomixer, the oil phase is gradually added to emulsify and
After processing with a homomixer at 1,000 rpm for 1.5 minutes, 6
After stirring and cooling to 5 ° C, add the microemulsion prepared above and perform treatment at 6,000 rpm for 1.5 minutes, cool to 25 ° C, and add a viscosity of 700,000 cp containing indomethacin to supersaturation.
An emulsion composition of s was obtained.

Example 3% 1 β-glycyrrhetinic acid 1.0 2 diphenhydramine 0.5 3 crotamiton 5.0 4 glycerin monocaprylate 5.0 5 propylene glycol dicaprylate 10.0 6 liquid paraffin 0.3 7 POE (55) molstearyl alcohol ether 2.0 8 propylene glycol 8.0 9 polyethylene glycol 400 5.0 19 'Purified water Suitable amount 10 Cetyl alcohol 5.0 11 Stearic acid 2.0 12 Trifat T-42 2.0 (manufactured by Nikko Chemical Co., Ltd.) 13 Vitamin E acetate 0.5 14 Isopropyl myristate 3.0 15 Glycerin monostearate 3.0 16 Hydrogenated soybean lecithin 0.1 17 Ethylparaben Proper amount 18 Potassium hydroxide 0.1 19 Purified water 47.5 (Production method) Add component 1 to components 3, 4 and 5 and heat to dissolve components 2 and 6
Was added and the temperature was adjusted to 40 ° C. to prepare an oil phase. On the other hand, the component (7) was added to the components 8, 9 and 19 'and dissolved, and the temperature was adjusted to 40 ° C to prepare an aqueous phase. Then add the oil phase to the water phase while processing at 10,000 rpm using a 1/4 HP homomixer and
After the treatment for a minute, the treatment was further conducted 8 times at 200 kg / cm ² using a Manton Gaulin homogenizer to obtain a target microemulsion having a particle diameter of 0.2 μm.

Separately, components 10, 11, 12, 13, 14, 15, 16, 17 were heated and dissolved at 70 ° C. to prepare an oil phase. On the other hand, component 18 was added to component 19 and dissolved, heated to 70 ° C., the oil phase was added to this and emulsified, and 10,000 rpm at a 1/4 PH homomixer was used for 1.5 minutes before preparation. The microemulsion described above was added, and the mixture was further treated at 6,000 rpm for 1.5 minutes and cooled to 25 ° C. to obtain an emulsion composition containing β-glycyrrhetinic acid in a supersaturated state.

Comparative Example 1 (1) Tolnaftate 2.0% (2) Diethyl phthalate 13.0 (3) Olive oil 6.0 (4) Liquid paraffin 1.0 (5) POE (80) Molar hydrogenated castor oil derivative 3.0 (6) Propylene glycol 10.0 (7) Glycerin 4.0 (8) Purified water 61.0 (9) Preservative A suitable amount (Production method) Add component (1) to component (2) and heat to dissolve, then add components (3) and (4) and cool to 40 ° C to obtain oil. Phased.
On the other hand, the component (5) was dissolved in the components (6) and (7), the components (8) and (9) were added, and the temperature was adjusted to 40 ° C to prepare an aqueous phase. Next, while adding the oil phase to the aqueous phase, a homomixer was used for preliminary emulsification, and the treatment was performed at 10,000 rpm for 2 minutes, and then using a Manton Gaulin homogenizer, 400 k
The microemulsion of Comparative Example having a particle diameter of 0.1 μ was obtained by treating 8 times with g / cm ² .

Component 1 was added to component 2 and dissolved by heating, then components 3 and 4 were added and the temperature was adjusted to 40 ° C. to prepare an oil phase. On the other hand, the component 5 was dissolved in the components 6, 7, and 12 ', and the temperature was adjusted to 40 ° C to prepare an aqueous phase. While processing at 1/4 HP homomixer, 10,000 rpm, pre-emulsify by adding the oil phase to the water phase, and further using a Manton Gaulin homogenizer 200 kg / cm ²
6 times to obtain a microemulsion of Comparative Example 2 having a particle size of 0.4μ. Microemulsions obtained in the same manner were each solidified with Veegum S-6198 and carboxyvinyl polymer, and the emulsified composition of Comparative Example 3 having a hardness of 55 / RT (card tension meter, 8φ, load of 200 g) and Comparative Example 4 were used. An emulsion composition having a viscosity of 55,000 cps was obtained.

[Effect of the Invention] The crystalline drug-containing emulsion composition according to the present invention has not only excellent physical stability over time, but also remarkably excellent transdermal absorbability.

It is also excellent in usability and safety.

The stability over time will be described below. An emulsion composition having a viscosity of 200,000 cps or more prepared by blending the O / W microemulsion containing the crystalline drug of Examples 1 to 3 according to the present invention was prepared. Even after the lapse of 6 months, no precipitation of crystals was observed and it was extremely stable. Also, in the emulsion composition which had been stored for 2 months under severe conditions (40 ° C., 0 ° C., −5 ° C.), crystals of each drug were not observed at all and were extremely stable.

The results are shown in Table-1.

◯: No crystal precipitation was observed.

X: Crystal precipitation was observed.

RT ·· room temperature It was confirmed by conducting an animal experiment with the indomethacin preparation of Example 2 that the crystalline drug-containing emulsion composition according to the present invention has remarkably better absorbability than that of the conventional emulsion base. .

(Test method) Rats are Crj: CD (SD) male rats 6 weeks old and weigh 180-220.
After transdermal administration of each sample using g, the plasma concentration of indomethacin and the residual amount of skin were measured over time.

After collecting blood, indomethacin in plasma was placed in a vacuum voting tube containing sodium heparin and centrifuged, and the obtained indomethacin was measured by Shimadzu Infarction Liquid Chromatography (HLPC).

As for the amount of remaining skin, 0.2 g of the sample was rubbed into the size of the rat's back 4 × 4 cm with reference to the method of Astier and Cooper, etc.
Bleeding and lethal at each time point, including application area 4 x 4 cm 6
The skin having a size of × 5 cm was cut off, peeled off, and measured by HLPC using those frozen and stored at 20 ° C. until quantification.

After application, the preparation of Example 2 had a gradually increased plasma concentration and reached the maximum value in 24 hours. In addition, the commercially available cream preparation has a low plasma concentration and hardly rises until 8 hours after application.
After 24 hours, the maximum value was obtained in the same manner as in Example 2 after removal.

On the other hand, with respect to the residual amount of skin, in the commercially available cream preparation, 80% or more of the applied amount remains on the skin up to 8 hours after application, the residual amount decreases from the 8th hour, and about 24 hours after application,
It is 28%.

In the formulation of Example 2 of the present invention, surprisingly, after application 1
It was confirmed that the residual amount of skin was already about 26% at the time point and gradually decreased thereafter, and about 16% at 24 hours, the transdermal absorbability was extremely good.

The results of measuring the concentration of indomethacin in plasma are shown in FIG. 1, and the results of measuring the residual skin rate are shown in FIG.

[Brief description of drawings]

FIG. 1 is a measurement result of indomethacin concentration in plasma when indomethacin was transdermally administered by the emulsion composition of the present invention, and FIG. 2 is a measurement result of indomethacin skin residual rate at that time.

Claims (38)

[Claims] 1. An O / W emulsion obtained by adding an O / W microemulsion containing a crystalline drug in a supersaturated state to an O / W emulsion prepared separately. 2. The O / W emulsion according to claim 1, wherein the crystalline drug contained in the O / W microemulsion is an anti-inflammatory agent. 3. The O / W emulsion according to claim 1, wherein the crystalline drug is an antifungal agent. 4. The O / W type emulsion according to claim 1, wherein the crystalline drug is a cardiotonic drug. 5. The anti-inflammatory agent is indomethacin, mefenamic acid, flufenamic acid, ketoprofen, diclofenac, glycyrrhizic acid, prednisolone, dexamethasone, betamethasone, dexamethasone acetate, beclomethasone propionate or prednisolone valerate acetate. The O / W type emulsion described in the item. 6. The O / W emulsion according to claim 3, wherein the antifungal agent is tolnaftate, griseofulvin, clotocumazole, ketoconazole, tricyclate or miconazole. 7. The O / W type emulsion according to claim 4, wherein the cardiotonic agent is ubidecarenone. 8. The O / W type emulsion according to any one of claims 1 to 7, wherein the O / W type microemulsion contains a surfactant, oil and water. 9. The O / W according to claim 8, wherein the surfactant contained in the O / W type microemulsion is a nonionic surfactant, an ionic surfactant or an amphoteric surfactant. W type emulsion. 10. The O / W type emulsion according to claim 9, wherein the nonionic surfactant is a polyoxyalkylene type, polyglycerin fatty acid ester, tween type or sugar ester. 11. The ionic surfactant is a fatty acid soap, an alkyl sulfonate, an alkyl phosphate, an ether phosphate, a fatty acid salt of a basic amino acid, triethanolamine soap or an alkyl quaternary ammonium salt. 10. An O / W emulsion according to item 9 above. 12. The O / W emulsion according to claim 9, wherein the amphoteric surfactant is betaine or an aminocarboxylic acid salt. 13. The surfactant according to claim 9, wherein the surfactant contained in the O / W microemulsion is a hydrophilic surfactant having HLB of 12 or more.
O / W type emulsion. 14. The oil component contained in the O / W type microemulsion is a lower dialkyl ester, triglyceride, synthetic oil, higher alcohol, higher fatty acid, liquid paraffin, squalane or silicone oil. An O / W emulsion according to any one of 1 to 13. 15. The O / W emulsion according to claim 14, wherein the lower dialkyl ester is adipic acid, pimelic acid, azelaic acid, sebacic acid or phthalic acid. 16. The triglyceride is olive oil, soybean oil, rapeseed oil, coconut oil or beef tallow.
The O / W emulsion according to item 14. 17. The O / W type emulsion according to claim 14, wherein the synthetic oil is oleyl oleate, decyl oleate, isopropyl myristate or isopropyl palmitate. 18. The method according to claim 14, wherein the higher alcohol is oleyl alcohol or octadecyl alcohol.
The O / W type emulsion described in the item. 19. The O / W emulsion according to claim 14, wherein the higher fatty acid is oleic acid or isostearic acid. 20. The O / W emulsion according to any one of claims 8 to 19, wherein the oil contained in the O / W microemulsion is liquid at room temperature. 21. The O / W type emulsion according to any one of claims 8 to 20, wherein a polyhydric alcohol is further added to the O / W type microemulsion. 22. The polyhydric alcohol contained in the O / W microemulsion is glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol or mannitol. The O / W type emulsion according to item 21. 23. The emulsification of an O / W microemulsion,
The O / W emulsion according to any one of claims 8 to 22, which is carried out by an ultrasonic emulsifier, Mantongaurin or a microfluidizer. 24. The amount of crystalline drug, surfactant and oil content in the O / W type microemulsion is 0.05 respectively.
The O / W emulsion according to any one of claims 8 to 23, wherein the O / W emulsion is -10% by weight, 0.5-20% by weight, and 5-70% by weight. 25. The O / W emulsion prepared separately is an O / W emulsion composed of a surfactant, an oil and water, and the emulsion according to any one of claims 1 to 24. O / W type emulsion. 26. The O / W emulsion according to claim 25, wherein the surfactant of the O / W emulsion prepared separately is a surfactant having a liquid crystal structure. 27. A surfactant capable of having a liquid crystal structure is stearic acid monoglyceride, palmitic acid monoglyceride, behenic acid monoglyceride, batyl alcohol, chimyl alcohol, polyoxyethylene hydrogenated castor oil derivative, sorbitan monostearate, sorbitan monopalmi. 27. The O / W type emulsion according to claim 26, which is tate or sorbitan monomyristate. 28. In an O / W type emulsion prepared separately,
Claim 26, further comprising a hydrophilic surfactant
The O / W emulsion according to the item. 29. The O / W emulsion according to claim 28, wherein the hydrophilic surfactant is a nonionic surfactant, an ionic surfactant or an amphoteric surfactant. 30. The O / W emulsion according to claim 29, wherein the ionic surfactant is fatty acid soap, triethanolamine soap or basic amino acid soap. 31. The O according to any one of claims 25 to 30, wherein the oil component in the separately prepared O / W emulsion is an oil component that can be hydrated with water to form a liquid crystal structure. / W type emulsion. 32. An oil capable of forming a liquid crystal structure when hydrated with water is higher alcohol, fatty acid, cholesterol, fatty acid triglyceride, isopropyl myristate, isopropyl palmitate, decyl oleate, liquid paraffin, squalane or silicone oil. 31. An O / W type emulsion according to claim 31. 33. The amount of surfactant and oil in the separately prepared O / W emulsion is 0.5 to 20% by weight, and 5 respectively.
The O / W emulsion according to any one of claims 1 to 32, wherein the O / W type emulsion is from 70 to 70% by weight. 34. The method according to any one of claims 1 to 33, wherein the amount of the O / W type microemulsion is 5 to 70% by weight based on the amount of the separately prepared O / W type emulsion. The described O / W emulsion. 35. The O / W emulsion according to any one of claims 1 to 34, wherein the emulsified particle diameter of the O / W microemulsion is 0.5 μm or less. 36. An emulsified particle size of an O / W type emulsion prepared separately is 1 to 5 .mu.
The O / W type emulsion according to any one of items. 37. The viscosity of the O / W emulsion is 200,000 cps.
(Vismetron VH type) The above is the O / W type emulsion according to any one of claims 1 to 36. 38. The viscosity of the O / W emulsion is 300,000 cps.
(Vismetron VH type) The above is the O / W type emulsion according to any one of claims 1 to 36.