JPS63150221A - Emulsified composition containing crystalline drug - Google Patents

Abstract

PURPOSE:To obtain the titled composition having excellent stability with time and high transcutaneous absorbability and useful as a drug, quasi-drug, cosmetic, etc., by compounding an O/W-type emulsion with another O/W-type emulsion containing a crystalline drug. CONSTITUTION:An O/W-type emulsion containing a crystalline drug such as anti-inflammatory agent (e.g. indomethacin), an antimycotic agent (e.g. tolnaftate) and a cardiotonic agent (e.g. ubidecarenone) in super-saturated state is added to a separately prepared O/W-type emulsion. The crystalline drug is emulsified by this process to micro-emulsion having an average particle diameter of <=0.5mu. The emulsification is carried out with an emulsifier while adding a surfactant (e.g. fatty acid soap), oil and, if necessary, a polyhydric alcohol at 50-70 deg.C. The amounts of the crystalline drug, the surfactant and the oil are 0.05-10wt.%, 0.5-20wt.% and 5-70wt.%, respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pharmaceutical product comprising an O/W type dichroic emulsion containing a crystalline drug in a supersaturated state in an O/W type emulsion; The present invention relates to an O/W emulsion useful in the fields of quasi-drugs and cosmetics. Note that the term "crystalline drug" as used herein means a drug that is insoluble in water, and does not include water-soluble drugs.

[Prior Art] In general, ointment bases, liquid formulations, and emulsion bases have often been used to formulate water-insoluble crystalline drugs.

In particular, when compounding a crystalline drug into an emulsion, it is necessary to make the crystal into microcrystals, clathrate it with cyclodextrin, etc., take advantage of crystal transition, or make it highly water-soluble in order to increase the transdermal absorption of the drug. Efforts have been made to create complexes by combining molecules, and to incorporate transdermal absorption enhancers such as eisin, oleyl alcohol, medium-chain triglycerides, and sodium pyrrolidone carboxylate, but transdermal absorption is still not sufficient. None of them are necessarily satisfactory in terms of skin irritation and stability.

[Problems to be Solved by the Invention] To emulsify a crystalline drug, it is possible to finely crush the crystals and blend them to increase transdermal absorption. It is better to dissolve it in oil and make it into a molecular form. Crystalline drugs generally dissolve in relatively highly polar oils, but not in non-polar oils; on the other hand, highly polar oils have poor emulsion stability.

In addition, in order to improve the release of the drug from the base, it is desirable to increase the concentration of the drug in the oil phase to at least the saturation solubility; however, if it exceeds the saturation solubility, drug crystals will inevitably precipitate in the base. I end up.

For liquid drugs and drugs with low melting points, it is relatively easy to blend drugs to near saturated solubility, but it is necessary to stably blend highly crystalline drugs (melting point of 60°C or higher) in a supersaturated state. I couldn't.

[Means for Solving the Problems] In view of the above circumstances, the present inventors have made efforts to obtain a crystalline drug'-containing emulsion composition that is excellent in stability, skin safety, percutaneous absorption, and ease of use. As a result of repeated research, we have found that by pre-preparing an O/W type microemulsion containing a supersaturated crystalline drug and then adding this microemulsion to another O/W type emulsion, good transdermal absorption can be achieved. The present invention was completed based on the discovery that it is possible to obtain an emulsified composition that has good stability and is also satisfactory in terms of skin irritation and feel when used.

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

The present invention will be explained in detail below.

The crystalline drug used in the present invention is a water-insoluble drug, such as indomethacin, mefenamic acid, flufenamic acid, ketoprofen, diclofenac, glycyrrhizic acid, prednisolone, dexamethasone, hetamethacin, dexamethasone acetate, beclomethasone propionate,
Examples include anti-inflammatory agents such as prednisolone valerate, antifungal agents such as tolnaftate, griseofulvin, clotocumazole, ketoconazole, tricyclate, and miconazole, and cardiotonic agents such as ubidecarenone.

In the present invention, the crystalline drug has an average particle size of 0.5 μm.
Emulsify into a microemulsion.

The emulsification method is not particularly limited, but preferably HLB
It is preferable to emulsify using a hydrophilic surfactant having 12 or more.

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

The oils that contain the above drugs in a supersaturated state and are to be emulsified in water by the surfactant include lower dialkyl esters such as adipic acid, pimelic acid, azelaic acid, sebacic acid, and phthalic acid, olive oil, soybean oil, Triglycerides such as rapeseed oil, coconut oil, and 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; Examples include oils such as paraffin, squalane, and silicone.

Preferably, those exhibiting a liquid state at room temperature are preferred.

For emulsification, we use ultrasonic emulsifiers, Manton Galarin,
It is preferable to use a compatible emulsifier such as a microfluidizer, and a microemulsion with a fine particle size can be easily obtained.

In addition to the crystalline drug, surfactant and oil, the emulsified composition may contain, for example, glycerin, propylene glycol, 1.
It is more preferable to blend polyhydric alcohols such as 3-butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol, mannitol, etc. from the viewpoint of production and stability of the microemulsion.

It is preferable to use a single surfactant, but two or more surfactants may be used in combination.

As the oil component, one or more of the above-mentioned oils may be appropriately selected and used.

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

That is, the crystalline drug O, OS is ~10% by weight, the surfactant is 0.5~20% by weight, and the oil content is 5~70% by weight.

If polyhydric alcohol is further added, 5 to 50% by weight
Good.

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

The O/W type emulsion is not particularly limited, but a surfactant that easily forms a liquid crystal structure is preferably used. Lipophilic surfactants include stearic acid monoglyceride, palmitic acid monoglyceride, hehenic acid monoglyceride, batyl alcohol, chimyl alcohol, polyoxyethylene hydrogenated castor oil derivatives, sorbitan monostearate, sorbitan monopalmitate, sorbitan monomyristate, etc. It is preferable to use it in combination with a hydrophilic surfactant. Although nonionic surfactants and amphoteric surfactants can be used as the hydrophilic surfactant, ionic surfactants such as fatty acid soap, triethanolamine soap, and basic amino acid soap are preferred.

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

The manufacturing method is arbitrary.

Both the surfactant and the oil can be used by appropriately selecting one or more of the above-mentioned ones.

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

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

In the O/W emulsion thus obtained, the above-mentioned O
/W-type microemulsion is added and blended.

The amount of the O/W type microemulsion to be blended is 5 to 70% (wt%) based on the amount of the O/W type emulsion.

The blending method is not particularly limited. Preferably 50-7
It is preferable to add the mixture with stirring at a temperature of 0°C and quickly cool it to room temperature.

The O/W type emulsion containing the ○/W type microelusion prepared in this way has a viscosity of 200,000 cps.
(measured with Bismetron VH type) or more is preferable. More preferably, it is 300,000 cps or more.

As described above, the present invention provides an O/W type emulsion containing a crystalline drug in a supersaturated state.

This is an O/W type emulsion containing a chloe emulsion, and is superior to any conventional skin preparation for external use in terms of stability, percutaneous absorption of drugs, and safety to the skin.

If the internal phase ratio of the 0/W type microemulsion is increased to increase the viscosity of the system, an emulsified composition with a viscosity comparable to that of the emulsified composition of the present invention can be obtained, but the oil content will be increased, resulting in poor usability. Not only is this undesirable, but the transdermal absorption of the crystalline drug is not improved, and the crystalline drug immediately precipitates out. Furthermore, the same effect can be achieved even if the outer phase of the O/W type microemulsion is hardened with a mineral thickener such as bentonite or a water-soluble thickener such as polyvinyl alcohol.

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

The O/W emulsion according to the present invention may contain various ingredients commonly used in pharmaceuticals and cosmetics, such as water-soluble drugs, to the extent that the effects of the present invention are not impaired, as necessary.
Oil-soluble drugs, absorption enhancers, powder components, thickeners, aquatic components, preservatives, antioxidants, fragrances, coloring agents, and the like can be blended. These may be mixed in advance into an O/W type dichroic emulsion, or may be blended into an O/W type emulsion.

〔Example〕

Next, the present invention will be explained in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

In addition, in the following examples, "%" indicates "weight %" unless otherwise specified. In addition, the particle size measurement of microemulsions is performed using the Nicomp Model 270 () IIACROY
(manufactured by CO), and the viscosity was measured with.

Example 1 1 Tolnaftate 2.0%2
Diethyl phthalate 13.03 Olive oil 6.04 Liquid paraffin 1.05 POE (
80 mol) Hydrogenated castor oil derivative 3.06 Propylene glycol 10.07 Glycerin
4.015” Purified water
Appropriate amount 8 cetanol
3.09 Stearic acid
2.010 Miglyol 812 1
．． 0% (manufactured by Dynamite Nobel) 11 Glycerin monostearate 3.01
2 Ethylparaben serving amount 13
Potassium hydroxide 0.114
Carboxyvinyl polymer 0.0515
Purified water 51.75 (manufacturing method) Component 1 was added to component 2, heated and melted, and then cooled to 40° C., and components 3.4 were sequentially added thereto to prepare an oil phase. On the other hand, component 5.15 was added to component 6.7 and melted under 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 emulsification was carried out for 2 minutes using a Manton Galarin homogenizer.
kg/c+J 10 times to obtain the desired microemulsion with a particle size of 0.1μ.

Separately, components 8.9.10.11.12 were heated and melted at 70°C to prepare an oil phase. -Add force component 1513 to 70
The aqueous phase was prepared by heating to °C. adding the oil phase to the water phase;
Emulsify, add component 14 dissolved in advance, process for 2 minutes at 10.00 rpm using a homomixer, add the microemulsion prepared previously, and process for 6 minutes using a homomixer. .00Orpm, 2
The mixture was treated for 1 minute and cooled to 25° C. with stirring to obtain an emulsion composition containing tolnaftate in a supersaturated state and having a viscosity of 350,000 cps.

Example 2 1 Indomethacin 1.0% 2 Diethyl phthalate 13.03 Miglyol 812 6.0 (manufactured by Dynamite Nobel) 4 Liquid paraffin 0.55 Decaglycerin monooleate 2.06 Glycerin
5.07113-Butylene glycol
7.016゛Oval water
Appropriate amount 8 Cetyl alcohol 4.09
Stearic acid 3.010 Glycerin monostearate 2.511 Isopropyl myristate 4.012 Dimethylpolysiloxane 2.013 Ethylparahen
Capacity 14 Begum S-6198O
, 3% (manufactured by Bang-Bilt) 15 Potassium hydroxide 0.157
° 1,3-butylene glycol 3. O12
Purified water 49.55 (manufacturing method) After adding component 1 to component 2 and heating and melting, add component 3.4
were added sequentially to prepare an oil phase. On the other hand, replace component 5 with component 6.
．． After dissolving in Component 7, component 16 was added to prepare an aqueous phase. Next, the oil phase was gradually added to the aqueous phase and treated for 5 minutes using a Polytron emulsifier to obtain a microemulsion containing supersaturated indomethacin with a particle size of 0.4 μm.

Separately, heat ingredients 8.9.10.11.12.13 at 75°C.
An oil phase was prepared by heating and dissolving the mixture. -Force components 14.15.
Add 7゛ to component 16 and heat to 75℃ for 1/4 H.
After dispersing using a P-Homo mixer, the oil phase was gradually added to emulsify, and the mixture was treated with a P-Homo mixer at 1 OOO rpm for 1.5 minutes, then stirred to 65°C. After cooling, the previously prepared micromulsion was added and treated at 6.00 rpm for 1.5 minutes, and cooled to 25°C to obtain an emulsion composition containing supersaturated indomethacin and a viscosity of 700,000 cps.

Example 3 %1 β
Glycyrrhetinic acid 1.02 Diphenhydramine 0.53 Crotamiton 5.04 Glycerin monocaprylate 5.05 Propylene glycol caprylate 10.06 Liquid paraffin
0.37 FOE (55) Molstearyl alcohol 2.0 Ether 8 Propylene glycol 8.09
Polyethylene glycol 400 5.019゛Oval water Appropriate amount 10 Cetyl alcohol 5.011 Stearic acid 2.012 Trifat T-422.0 manufactured by Nikko Chemical Co.) 13 Vitamin E acetate 0.5
14 Isopropyl myristate 3.0
15 Glycerin monostearate 3.0
16 Hydrogenated soybean lecithin 0.1
17 Ethylparahen appropriate amount 1
8 Potassium hydroxide 0.11
9 Purified water 47.5
(Production method) Add component 1 to component 3.4.5 and heat and melt to obtain component 2.6.
was added and the temperature was adjusted to 40°C to prepare an oil phase. On the other hand, add component (7) to component 8.9.19' and dissolve at 40°C.
The temperature was adjusted to prepare an aqueous phase. Next 1/4 up
10. Using a homo mixer. After processing with OOOrpm, the oil phase was added to the aqueous phase and treated for 3 minutes, and then using a Manton Galarin homogenizer at 200 kg/cu.
The treatment was carried out 8 times at t to obtain the target microemulsion with a particle size of 0.2μ.

Separately, ingredients 10.11.12.13.14.15.16
．． No. 17 was heated and melted at 70°C to prepare an oil phase. on the other hand,
Add component 18 to component 19, melt and heat to 70°C.
Add the oil phase to this and emulsify it, using a 1/4 PH homomixer for 10. OOOrpm for 1.5 minutes, add the microemulsion prepared earlier, and further 6. OOOrpm for 1.5 minutes and cooled to 25° C. to obtain an emulsified 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
+51 POE (8O) molar hydrogenated castor oil derivative
3.0 (6) Propylene glycol 1
0.0(7) Glycerin 4
．． 0(8) Purified water 61
．． 0(9) Preservative Amount (manufacturing method) Component (1) was added to component (2) and dissolved by heating, then components (3) and (4) were added and cooled to 40° C. to form an oil phase.

On the other hand, component (5) is dissolved in components (6) and (7), and component (
8) and (9) were added, the temperature was adjusted to 40°C, and the aqueous phase was screened.

Next, add the oil phase to the aqueous phase while using a homomixer for pre-emulsification 10. OOOrpm, treated for 2 minutes, and further incubated for 4 minutes using a Manton Galarin homogenizer.
A microemulsion of a comparative example with a particle size of 0.1 μm was obtained by treating the sample 8 times at 0.00 kg/ca.

Comparative Example Comparative Example Comparative Example'1 Indomethacin 1.0 1.0 1.
02 Diethyl phthalate 13.0 13.0 1
3.03 Miglyol 812 6.0 '6.
0 6.0 (manufactured by Dynamite Nobel) 4 Crystor 172 0.5 0.5 0.5
5 Decaglycerin mono 2.0 2.0 2.0
Olate 61.3-butylene glyco? ,0 7.0 7.
0-Lua Glycerin 5.0 5.0 5.01
4” Purified water Appropriate amount Appropriate amount Volume 9 Veegum S-6198-4,0- (manufactured by Pandabilt) 10 Lactic acid -0,11,011 carboxyvinyl -0,6 Polymer 12 Potassium hydroxide -0,213 Preservative
Appropriate amount Appropriate amount Volume 14 Purified water
65.5 61.4 63.7 (Production method) Component 1 was added to component 2 and heated and melted, then component 3.4 was added and the temperature was adjusted to 40° C. to prepare an oil phase. Separately, component 5 was dissolved in component 6.7.12'' and the temperature was adjusted to 40°C to prepare an aqueous phase. 1/4 HP homomixer, 10
．． The microemulsion of Comparative Example 2 with a particle size of 0.4μ was obtained by adding the oil phase to the aqueous phase for pre-emulsification while processing at OOO rpm, and further processing 6 times at 200 kg/ca using a Manton Galarin homogenizer. I got it. The microemulsions obtained in the same manner were solidified with Veegum S-6198 and carboxyvinyl polymer to form an emulsion composition of Comparative Example 3 with a hardness of 55/RT (card tension meter, 8φ, 200g load) and Comparative Example 4. An emulsion composition having a viscosity of 55.0OOcps was obtained.

[Effects of the Invention] The crystalline drug-containing emulsion composition according to the present invention not only has excellent physical stability over time, but also has the advantage of remarkably good percutaneous absorption.

It also has excellent usability and safety.

Regarding stability over time, emulsion compositions having a null viscosity of 200,000 cps or more obtained by blending the O/W microemulsions containing the crystalline drugs of Examples 1 to 3 according to the present invention are as follows: Even after 6 months had passed since preparation, no crystal precipitation was observed and the product was extremely stable. Furthermore, the emulsion compositions that had been used under severe conditions (40°C, 0°C, -5°C) for 2 months were also extremely stable, with no crystals of the respective drugs observed.

These results are shown in Table-1.

(Margin below) Table - ■ (Margin below) 0: No crystal precipitation was observed.

x: Crystal precipitation was observed.

RT: room temperature Next, an animal experiment was conducted using the indomethacin formulation of Example 2 to confirm that the crystalline drug-containing emulsion composition according to the present invention has significantly better absorption than that of a conventional emulsion-based emulsion composition. .

(Test method) Rats were Crj: CD' (SD) male rats, 6 weeks old and weighing 180 to 220 g. Each sample was administered transdermally, and the plasma concentration and skin residual of indomethacin were determined over time. The amount was measured.

Indomethacin in plasma was obtained by centrifugation in a vacuum blood collection tube containing heparin sodium after blood collection, and the indomethacin obtained by Shimadzu infarct liquid chromatography (HL).

PC).

In addition, to determine the amount of remaining skin, 0.2 g of the sample was placed on the back of the rat 4 x 4 according to the method of Astier and Cooper et al.
cm in size, and bled to death at each time point.
A 6 × 5 am skin area containing an application area of 4 × 4 cm was cut and peeled, and each was incubated for 20 days until the time of determination.
Measurement was performed by HLPC using samples stored frozen at ℃.

After application of the preparation of Example 2, the concentration in plasma gradually increased and reached the maximum level within 24 hours. In addition, the plasma concentration of commercially available cream preparations is low and hardly increases for up to 8 hours after application.
It gradually increased from the second hour and reached the highest value at 24 hours as in Example 2.

On the other hand, in terms of the amount remaining on the skin, for commercially available cream formulations, more than 80% of the applied amount remains on the skin up to 8 hours after application, and the remaining amount decreases from the 8th hour onwards, and is approximately 28% within 24 hours after application. It becomes.

The formulation of Example 2 of the invention surprisingly showed that after application 1
The amount remaining in the skin was already about 26% at the 24-hour mark, and after that it gradually decreased to about 16% at 24 hours, confirming that the transdermal absorption 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 rate in the skin are shown in FIG.

[Brief explanation of the drawing]

FIG. 1 shows the results of measuring indomethacin concentration in plasma when indomethacin was administered transdermally using the emulsified composition of the present invention, and FIG. 2 shows the results of measuring the skin residual rate of indomethacin at that time.

Claims (1)

[Scope of Claims] 1. An O/W emulsion obtained by adding an O/W microemulsion containing a crystalline drug in a supersaturated state to a separately prepared O/W emulsion. 2. The O/W type emulsion according to claim 1, wherein the crystalline drug contained in the O/W type microemulsion is an anti-inflammatory agent. 3 Claim 1 in which the crystalline drug is an antifungal agent
O/W type emulsion described in section. 4. The O/W emulsion according to claim 1, wherein the crystalline drug is a cardiotonic agent. 5. O according to claim 2, wherein the anti-inflammatory agent is indomethacin, mefenamic acid, flufenamic acid, ketoprofen, diclofenac, glycyrrhizic acid, prednisolone, dexamethasone, betamethasone, dexamethasone acetate, beclomethasone propionate, or prednisolone acetate valerate. /W type emulsion. 6 Antifungal agents include tolnaftate, griseofulvin,
O/ according to claim 3, which is clotocumazole, ketoconazole, tricyclate or miconazole.
W type emulsion. 7. The O/W 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 microemulsion according to claim 8, wherein the surfactant contained in the O/W microemulsion is a nonionic surfactant, an ionic surfactant, or an amphoteric surfactant.
/W type emulsion. 10 O/ according to claim 9, wherein the nonionic surfactant is a polyoxyalkylene type, a polyglycerin fatty acid ester, a Tween type, or a sugar ester.
W type emulsion. 11. Claim 9, wherein 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, a triethanolamine soap, or an alkyl quaternary ammonium salt.
O/W type emulsion described in section. 12. The O/W emulsion according to claim 9, wherein the amphoteric surfactant is betaine or an aminocarboxylic acid salt. 13. The O/W type emulsion according to any one of claims 9 to 12, wherein the surfactant contained in the O/W type microemulsion is a hydrophilic surfactant with an HLB of 12 or higher. 14 The oil contained in the O/W type microemulsion is lower dialkyl ester, triglyceride, synthetic oil, higher alcohol, higher fatty acid, liquid paraffin,
Claim 8 which is squalane or silicone oil
The O/W emulsion according to any one of Items 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 O/W emulsion according to claim 14, wherein the triglyceride is olive oil, soybean oil, rapeseed oil, coconut oil or beef tallow. 17 Synthetic oils include oleyl oleate, decyl oleate,
The O/W emulsion according to claim 14, which is isopropyl myristate or isopropyl palmitate. 18. The O/W emulsion according to claim 14, wherein the higher alcohol is oleyl alcohol or octadecyl alcohol. 19. The O/W emulsion according to claim 14, wherein the higher fatty acid is oleic acid or isostearic acid. 20. The O/W type emulsion according to any one of claims 8 to 19, wherein the oil contained in the O/W type 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 blended into the O/W type microemulsion. 22 The polyhydric alcohol contained in the O/W type microemulsion is glycerin, propylene glycol,
22. The O/W emulsion according to claim 21, which is 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, sorbitol or mannitol. 23. Claims 8 to 22, wherein the O/W microemulsion is emulsified using an ultrasonic emulsifier, a Manton-Gaulin machine, or a microfluidizer.
O/W type emulsion according to any one of paragraphs. 24 The amounts of crystalline drug, surfactant, and oil in the O/W microemulsion are each 0.05 to 0.05.
The O/W emulsion according to any one of claims 8 to 23, wherein the content is 10% by weight, 0.5 to 20% by weight, and 5 to 70% by weight. 25. The O/W emulsion according to any one of claims 1 to 24, wherein the separately prepared O/W emulsion is composed of a surfactant, oil, and water. emulsion. 26. The O/W emulsion according to claim 25, wherein the surfactant of the separately prepared O/W emulsion is a surfactant that can have a liquid crystal structure. 27 Surfactants capable of forming a liquid crystal structure include stearic acid monoglyceride, palmitic acid monoglyceride, behenic acid monoglyceride, batyl alcohol, chimyl alcohol, polyoxyethylene hydrogenated castor oil derivative,
27. The O/W emulsion according to claim 26, which is sorbitan monostearate, sorbitan monopalmitate or sorbitan monomyristate. 27. The O/W emulsion according to claim 26, wherein a hydrophilic surfactant is further blended into the separately prepared O/W emulsion. 28. The O/W emulsion according to claim 27, wherein the hydrophilic surfactant is a nonionic surfactant, an ionic surfactant, or an amphoteric surfactant. 29. The O/W emulsion according to claim 28, wherein the ionic surfactant is a fatty acid soap, a triethanolamine soap, or a basic amino acid soap. 30 The oil content in the separately prepared O/W emulsion is
The O/W emulsion according to any one of claims 25 to 29, which is an oil that can take a liquid crystal structure when hydrated with water. 31. Claim 30, wherein the oil that can take a liquid crystal structure when hydrated with water is a higher alcohol, fatty acid, cholesterol, fatty acid triglyceride, isopropyl myristate, isopropyl palmitate, decyl oleate, liquid paraffin, squalane, or silicone oil. O/W type emulsion described in section. 32 The amounts of surfactant and oil in the separately prepared O/W emulsion are 0.5 to 20% by weight and 5 to 20% by weight, respectively.
The O/W emulsion according to any one of claims 1 to 31, wherein the content is 70% by weight. 33 The amount of O/W type microemulsion is 5 to 70% by weight based on the amount of separately prepared O/W type emulsion.
An O/W emulsion according to any one of claims 1 to 32. 34 Emulsion particle size of O/W type microemulsion is 0
．． The O/W emulsion according to any one of claims 1 to 33, which has a particle size of 5μ or less. 35. The O/W emulsion according to any one of claims 1 to 34, wherein the separately prepared O/W emulsion has an emulsion particle size of 1 to 5 μm. 36 The viscosity of the O/W emulsion is 200,000 cps (
36. The O/W emulsion according to any one of claims 1 to 35, wherein the O/W type emulsion has a viscosity of at least 10% (measured with a Bismetron VH type). 37 The viscosity of the O/W emulsion is 300,000 cps (
36. The O/W emulsion according to any one of claims 1 to 35, wherein the O/W type emulsion has a viscosity of at least 10% (measured with a Bismetron VH type).