JP5026824B2 - Liquid crystal emulsified pharmaceutical composition containing cyclosporine - Google Patents

Description

  The present invention relates to a pharmaceutical composition for external application to the skin having excellent transdermal absorbability of cyclosporine and having an excellent therapeutic effect against various skin diseases such as allergic diseases and autoimmune diseases while having a low concentration.

  Cyclosporine suppresses rejection in organ transplantation such as kidney, liver, heart, lung, pancreas, rejection in bone marrow transplantation and graft-versus-host disease, Behcet's disease, severe aplastic anemia, nephrotic syndrome In addition to being used as oral preparations and injections, oral preparations are also used for severe psoriasis.

  It is also known to be effective for allergic diseases such as atopic dermatitis and various skin diseases such as autoimmune diseases.

  As mentioned above, cyclosporine is extremely effective, but cyclosporine oral drugs and injections have a very high incidence of systemic side effects such as renal dysfunction and many drug interactions with other drugs. In some cases, the use had to be restricted.

  For various skin diseases such as allergic diseases such as psoriasis and atopic dermatitis and autoimmune diseases, the therapeutic effect can be exerted by applying the cyclosporine preparation directly to the skin that is the disease site. By performing local treatment in this way, enhancement of drug efficacy and reduction in the incidence of systemic side effects can be expected due to increased drug concentration at the diseased site.

  Against this background, a treatment method for applying a cyclosporin preparation directly to a diseased site such as psoriasis or atopic dermatitis and absorbing it through the skin is attempted, and the development of an effective external preparation with few side effects as described above is desired. ing. However, since the molecular weight of cyclosporine is as large as 1,200, it is difficult to absorb percutaneously with a general external preparation, and it is difficult to exert a medicinal effect at a diseased site.

  As an attempt to percutaneously absorb cyclosporine, there is an external preparation containing a high concentration of cyclosporine. That is, an organic solvent for dissolving cyclosporine, a fatty acid ester of a monohydric alcohol having a total carbon number of 8 or more which is liquid at 25 ° C. and / or an alkanolamine which is liquid at 25 ° C., an oily property which is solid at 25 ° C. A topical agent comprising a substance and a surfactant (Patent Document 1), an organic liquid, an external agent containing a solid oily substance and a surfactant (Patent Document 2), a polycarboxylic acid polyalkyl ester that is liquid at room temperature, O. B. Is an oil-in-water emulsion composition containing a liquid oil and a surfactant at room temperature of 0 to 0.25 (Patent Document 3), a gel or ointment containing oleyl alcohol based on propylene glycol (Patent Document 4) Spontaneous emulsions (Patent Document 5) and colloidal pharmaceutical preparations (Patent Document 6) have been proposed. Since these external preparations contain cyclosporine at a high concentration, not only are there side effects associated with cyclosporine, but the blending ratio of the surfactant is poor because the blending ratio of oil or water-soluble polyhydric alcohol is high. It is a preparation that is high in skin irritation.

  On the other hand, an ointment in which the content of cyclosporine is reduced by using laurolyl sarcosine as an absorption promoter has been proposed (Patent Document 7). However, since an ointment base or oil is prepared as a base at a very high blending ratio, it is a preparation with a poor feeling of use.

Since an externally applied pharmaceutical composition is one of the important factors that the touch after application is good, neither external preparation is satisfactory as a pharmaceutical product.
Japanese Patent Laid-Open No. 5-310591 JP-A-7-188046 JP 7-278007 A JP-A-8-133799 Japanese Patent Laid-Open No. 10-7484 JP 2005-516931 A Japanese Patent Laid-Open No. 7-25784

  An object of the present invention is to provide a pharmaceutical composition for external use that enhances the transdermal absorbability of cyclosporine and exhibits a medicinal effect at a low concentration. It is another object of the present invention to provide a pharmaceutical composition for external use with excellent skin feel after application.

  As a result of diligent research on a composition suitable for an external skin pharmaceutical composition containing cyclosporine, the present inventors have obtained a medicinal effect even though the content of cyclosporin is small by using a liquid crystal emulsion type pharmaceutical composition. Succeeded in obtaining a pharmaceutical composition for external application to the skin.

  Further, by using a liquid crystal emulsion type pharmaceutical composition, even when cyclosporine is contained, a pharmaceutical composition for external use having an excellent feel after application at the time of application was successfully obtained.

That is, the present invention provides a liquid crystal emulsion type pharmaceutical composition containing cyclosporine and a nonionic surfactant.
Furthermore, the oil phase component constituting the liquid crystal emulsion type pharmaceutical composition of the present invention preferably contains an oil, a fatty acid that does not dissolve in the oil, and a solid higher alcohol that does not dissolve in the oil.
The aqueous phase component constituting the liquid crystal emulsified pharmaceutical composition of the present invention preferably contains a water-soluble polyhydric alcohol that is immiscible with oil.

  The liquid crystal emulsion type pharmaceutical composition of the present invention is characterized by the constitution of the oil phase component. That is, among the constituent components, fatty acids and solid higher alcohols are required not to be dissolved in a liquid oil component that is an oil component. Accordingly, it is desirable that the liquid oil component has a relatively low polarity. When the polarity of the liquid oil component is increased, fatty acids and higher alcohols are uniformly dissolved, and it becomes difficult to form a liquid crystal structure.

  By making the fatty acid and the solid higher alcohol insoluble in the liquid oil component that is an oil component, the fatty acid and the solid higher alcohol easily form an alignment state in the vicinity of the interface together with the nonionic surfactant. When a specific zwitterionic amino acid is added to this state, the interface is further stabilized, and the liquid crystal emulsion type pharmaceutical composition can be maintained in a more stable state in terms of formulation.

  In the present invention, the liquid crystal emulsification type pharmaceutical composition is a microscope (objective lens: objective lens: 40 times, eyepiece lens: 10 times). As a result, clear emulsified particles are not recognized and a simple deflection filter is attached (objective lens). : 4 to 40 times, eyepiece lens: 10 times) As a result of observation with an optical anisotropy, it refers to a composition that refracts light.

  Cyclosporin contained as an active ingredient is a known compound, and cyclosporin A, cyclosporin B, cyclosporin C, cyclosporin D, and cyclosporin H are known, and any of them can be used in the present invention, but cyclosporin A is preferred. These cyclosporine can be purchased as reagents from Alexis, MP Biomedicals, Inc., LKT Labs, Inc, Toronto Research Chemicals Inc, and the like. The amount of cyclosporine contained in the pharmaceutical composition of the present invention is not particularly limited as long as it is a therapeutically effective amount for the applied skin disease, but the content is 0 with respect to the total amount of the pharmaceutical composition obtained by the present invention. 0.01 to 1% by weight, preferably 0.05 to 0.75% by weight, more preferably 0.05 to 0.5% by weight.

  The surfactant that can be used in the present invention is a nonionic surfactant, and it is preferable to use a combination of a hydrophilic nonionic surfactant and a lipophilic nonionic surfactant.

  As the lipophilic nonionic surfactant, those having an HLB value of 2.0 to 7.0 are preferable. Specifically, glyceryl monostearate, sorbitan monostearate, diglyceryl monooleate, diglyceryl monostearate Glyceryl monostearate, polyoxyethylene behenyl ether, etc., preferably glyceryl monostearate, diglyceryl monostearate, tetraglyceryl monostearate, more preferably glyceryl monostearate, monostearate Tetraglyceryl acid. These can be used alone or in combination of two or more, and the blending amount is 0.1 to 5% by weight, preferably 0.5 to 4% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention. . If it is less than 0.1% by weight, the liquid crystal structure cannot be maintained, and if it exceeds 5% by weight, skin irritation tends to occur.

  As the hydrophilic nonionic surfactant, those having an HLB value of 10.0 to 18.0 are preferable. Specifically, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyoxyethylene cetyl ether, Examples thereof include polyoxyl stearate 25, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene hydrogenated castor oil 60 are preferable. These can be used alone or in combination of two or more, and the blending amount is 0.1 to 5% by weight, preferably 0.5 to 4% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention. . If it is less than 0.1% by weight, the liquid crystal structure cannot be maintained, and if it exceeds 5% by weight, skin irritation tends to occur.

  The oil phase component that can be used in the present invention is not particularly limited as long as it is generally used for external preparations and cosmetics, but is used in combination of at least an oil, a fatty acid that does not dissolve in oil, and a solid higher alcohol that does not dissolve in oil. It is preferable.

  Examples of oils that can be used in the present invention include hydrocarbons, fatty acid esters, triglycerides, and liquid higher alcohols. Examples of the hydrocarbon include squalane and liquid paraffin, examples of the fatty acid ester include octyldodecyl myristate, isopropyl myristate, and diethyl sebacate. Examples of the triglyceride include glycerol triisooctanoate, And chain fatty acid triglycerides. Liquid higher alcohols refer to higher alcohols that are liquid at room temperature, and specific examples include octyldodecanol and hexyldecanol, but are preferably squalane, glycerin triisooctanoate, and octyldodecanol. When an oil component that dissolves fatty acid and solid higher alcohol is used, it is difficult to maintain the liquid crystal structure. Therefore, it is necessary to select an oil component that does not dissolve fatty acid and solid higher alcohol at room temperature. These can be used alone or in combination of two or more thereof, and the blending amount thereof is 0.5 to 10% by weight, preferably 1 to 9% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention.

In the present invention, “does not dissolve in oil” means that the fatty acid or solid higher alcohol does not dissolve in the desired oil at room temperature, or the fatty acid or solid higher alcohol does not exceed the saturated solubility in the desired oil in the desired blending amount. Since it exists, it means that the oil and fatty acid or solid higher alcohol are not dissolved.
Moreover, in this invention, room temperature means 1-30 degreeC.

  Fatty acids that are not soluble in the oil that can be used in the present invention are preferably solid fatty acids at room temperature, and more preferably saturated and linear fatty acids having 16 to 22 carbon atoms. Specific examples include palmitic acid, stearic acid, behenic acid, and the like, preferably behenic acid. These can be used individually or in combination of 2 or more types, and the compounding quantity is 0.1 to 1 weight% with respect to the pharmaceutical composition whole quantity obtained by this invention.

  The solid higher alcohol that does not dissolve in the oil that can be used in the present invention refers to a higher alcohol that is solid at room temperature, specifically, a saturated, linear solid higher alcohol having 16 to 22 carbon atoms is preferred, Examples include cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol, and cetostearyl alcohol and behenyl alcohol are preferable. These can be used alone or in combination of two or more, and the blending amount is 0.1 to 10% by weight, preferably 0.5 to 6% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention. .

  The aqueous phase component that can be used in the present invention is not particularly limited as long as it is generally used for external preparations and cosmetics, but it is preferable to use a water-soluble polyhydric alcohol that is at least immiscible with oil.

  Examples of the water-soluble polyhydric alcohol that is immiscible with the oil that can be used in the present invention include 1,3-butylene glycol, glycerin, propylene glycol, dipropylene glycol, and the like, preferably 1,3-butylene glycol. Glycerin. These can be used alone or in combination of two or more kinds, and the blending amount is 1 to 50% by weight, preferably 5 to 50% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention.

  In the present invention, “immiscible with oil” means that a water-soluble polyhydric alcohol is not miscible with a desired oil at room temperature.

  An emulsion stabilizer can also be blended for stabilizing the liquid crystal structure. Examples of the emulsion stabilizer include L-arginine, glycine, sodium N-acyl-L-glutamate and the like, and L-arginine is preferable. These can be used alone or in combination of two or more, and the blending amount is 0.01 to 5% by weight, preferably 0.05 to 0.5% by weight, based on the total amount of the pharmaceutical composition obtained by the present invention. It is.

  Since the pharmaceutical composition of the present invention has a structural viscosity, it is not necessary to add a thickener or the like, but if necessary, a thickener such as a water-soluble polymer such as carboxyvinyl polymer or a viscous mineral such as bentonite is added. By blending, it can be adjusted to the desired viscosity.

  Furthermore, if necessary, pH regulators such as citric acid and sodium citrate, dyes, fragrances, pigments, preservatives, antioxidants, stabilizers, UV absorbers, etc. are appropriately blended within the range constituting this purpose. can do.

  In the pharmaceutical composition of the present invention, cyclosporine is present in a dissolved state in a solubilizer. As the cyclosporine solubilizer, any solubilizer capable of dissolving a required amount of cyclosporine can be used regardless of the oil phase component or the aqueous phase component, but α = 10 to 75 (α is organic / inorganic). Tan α representing the balance of sex) is preferred, and hexyl decanol, octyldodecanol, and 1,3-butylene glycol are more preferred.

  As a preferred embodiment, the liquid crystal emulsion type pharmaceutical composition of the present invention comprises 0.01 to 1% by weight of cyclosporine and 0.1 to 5% by weight of a hydrophilic nonionic surfactant based on the weight of the whole composition. 0.1 to 5% by weight of lipophilic nonionic surfactant, 0.5 to 10% by weight of oil, 0.1 to 1% by weight of fatty acid not dissolved in oil, 0.1 to 6% by weight of oil And a water-soluble polyhydric alcohol that is immiscible with 1 to 50% by weight of oil.

  In a more preferred embodiment, the liquid crystal emulsified pharmaceutical composition of the present invention comprises, based on the total weight of the composition, 0.05 to 1% by weight of cyclosporine, 0.5 to 5% by weight of glyceryl monostearate, 0% 5-5 wt% polyoxyethylene hydrogenated castor oil 60, 1-10 wt% squalane, 0.1-1 wt% behenic acid, 0.5-6 wt% cetostearyl alcohol, and 1-50 % By weight of glycerol and / or 1,3-butylene glycol.

  The method for producing the liquid crystal emulsified pharmaceutical composition of the present invention is not particularly limited, but includes oils, fatty acids that do not dissolve in oils, solid higher alcohols that do not dissolve in oils, lipophilic nonionic surfactants, hydrophilic non-ionic surfactants. By preparing a water phase containing an oil phase containing an ionic surfactant and the like and a water-soluble polyhydric alcohol that is immiscible with the oil, an amino acid, a pH regulator, water, etc., and adding the water phase to the oil phase A target liquid crystal emulsified pharmaceutical composition can be prepared during the emulsification process. Cyclosporine is used that has been previously dissolved in an oil or a water-soluble polyhydric alcohol that is not miscible with the oil. In addition, the aqueous phase for emulsification may be used all at once, or after partly emulsifying to form a concentrated emulsion (conc base), the remaining aqueous phase is divided into several stages. May be diluted by mixing with conc base. When dividing the water phase into several stages, after dissolving all the water phase components, a certain amount may be subdivided and emulsified. For example, amino acids may be added only to the aqueous phase at the time of making the base. It is good also as a water phase component of a different composition in a step and a dilution step.

  Various conditions for preparing the oil phase of the present invention are appropriately selected, but the oil, fatty acids that do not dissolve in the oil, solid higher alcohols that do not dissolve in the oil, lipophilic nonionic surfactants and hydrophilic nonionic surfactants In order to uniformly mix and dissolve the components, it is desirable to mix and dissolve each component at 60 to 90 ° C, preferably 65 to 85 ° C. If the temperature is too low, it may be difficult to uniformly mix and dissolve the oil phase, and if the temperature is too high, each component may be altered.

  The conditions for preparing the aqueous phase of the present invention are appropriately selected, but water appropriately selected from water-soluble polyhydric alcohols that are immiscible with oil, amino acids, pH regulators, preservatives, stabilizers, and the like. In order to uniformly mix and dissolve the phase components in water, it is desirable to mix and dissolve them at room temperature to 90 ° C, preferably from room temperature to 80 ° C.

  Next, the preparation of the concentrated emulsion (conc base) is to gradually add the aqueous phase to the oil phase while stirring the oil phase. The temperature at which the conc base is prepared is appropriately selected depending on the types of the oil phase and the aqueous phase, and is usually 50 ° C. to 90 ° C. at the start of stirring and room temperature at the end of stirring. If the temperature is too low, emulsification may be difficult.

  Various conditions for preparing the aqueous phase in the second step of the present invention are appropriately selected, but a preservative, a pH adjuster and a stabilizer are dissolved in water. In order to uniformly mix and dissolve these components, it is desirable to mix and dissolve at room temperature to 90 ° C, preferably from room temperature to 80 ° C. The aqueous phase and the concentrate base are uniformly mixed at room temperature, and further stirred and degassed to obtain the intended liquid crystal emulsion type pharmaceutical composition. The aqueous phase can be added at room temperature without the need for warming.

  The pharmaceutical composition of the present invention can be produced by using an emulsifier used for producing an ordinary pharmaceutical external preparation, but if necessary, a powerful stirrer such as a Menton Gaurine emulsifier or a microfluidizer You may manufacture using.

  In administration of the pharmaceutical composition of the present invention, the pharmaceutical composition is directly applied to the affected area several times a day, for example, 1 to 3 times, or processed into a form such as a patch, a plaster, a pap and the like. It can be applied to the affected area several times a day. The number of applications can be appropriately increased or decreased depending on the severity of the disease. The pharmaceutical composition of the present invention can be used for skin diseases in which cyclosporine is effective for treatment, such as atopic dermatitis and psoriasis.

  INDUSTRIAL APPLICABILITY According to the present invention, there is provided a pharmaceutical composition for an outer skin that can sufficiently exert its medicinal effects despite its low cyclosporine content. In addition, a pharmaceutical composition for external use with excellent skin feel after application is provided.

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

[Example 1] Preparation of liquid crystal emulsion composition Squalane, behenic acid, cetostearyl alcohol, glyceryl monostearate, polyoxyethylene (20) polyoxypropylene (4) cetyl ether having the composition ratio shown in Table 1 below. Was dissolved at 85 ° C. (oil phase). Cyclosporin A was dissolved in 1,3-butylene glycol at 60 ° C. (main drug phase). Further, a pH regulator, L-arginine was dissolved in water at 85 ° C. (aqueous phase). The main ingredient phase was added to the oil phase, and the aqueous phase was further added and stirred (conc base).

  Separately, 1,3-butylene glycol, a pH adjuster and water were added and dissolved at room temperature (post-added water phase). The post-added water phase was added to the conc base at room temperature, and stirring and deaeration were performed to obtain the intended preparation.

[Examples 2 to 10 and Comparative Example 1]
The preparation was prepared in the same composition ratio as shown in Table 1 by operating in the same manner as in Example 1.

[Comparative Example 2]
Protopic (registered trademark) ointment 0.1%; ointment containing 1.02 mg of tacrolimus hydrate (manufactured by Astellas Pharma Inc.)

[Test Example 1] Emulsified state and emulsified particle diameter A small amount of the preparations of Examples 1 to 10 were placed on a slide glass and covered with a cover glass, followed by microscopic observation (objective lens: 40 times, eyepiece: 10 times). Carried out. Further, if necessary, the presence or absence of optical anisotropy was also observed using a simple polarizing filter (objective lens: 4 to 40 times, eyepiece: 10 times).

<Evaluation criteria>
A: Recognized light due to optical anisotropy is recognized without clear emulsified particles.
B: Only emulsified particles of 1 μm or less C: Only emulsified particles of 1 to 5 μm D: Emulsified particles of 1 to 5 μm mainly including particles of several to several tens of μm E: Others

  Each of the compositions of the examples did not recognize clear particles, but refracted light due to optical anisotropy, and was confirmed to be a liquid crystal emulsion composition.

[Test Example 2] Formulation stability test The formulation of Example 6 was stored for 3 weeks under the conditions shown in Table 3, and the presence or absence of crystal precipitation was examined with a microscope (objective lens: 40 times, eyepiece: 10 times). The presence or absence of separation of the preparation was confirmed visually.
The results are shown in Table 3, and it was confirmed that the preparation was stable without crystal precipitation even when stored under any conditions.

[Test Example 3] Main drug stability test The content of cyclosporin A when the preparation of Example 6 was stored for 3 weeks under the conditions shown in Table 4 was measured. The cyclosporin A content was measured by adding a tetradecanophenone solution and acetonitrile to about 0.6 g of the preparation and stirring, and then using a part of the supernatant obtained by centrifugation as a sample solution. The content of cyclosporin A contained in each sample was measured by reverse-phase high performance liquid chromatography (detection wavelength: 210 nm, mobile phase; water: acetonitrile mixture = 2: 3), and the residual ratio of cyclosporin A relative to the initial value. (%) Was calculated.
The results are shown in Table 4, and it was confirmed that cyclosporin A was a stable preparation even when stored under any conditions.

[Test Example 4] Pharmacological test A pharmacological test was conducted on the preparations of Examples 1 to 5, Comparative Example 1 and Comparative Example 2. 0.1 mL of a 3% picryl chloride / ethanol solution was applied to the abdomen of a mouse shaved from the abdomen (sensitization). Six days later, 0.02 mL of 1% picryl chloride / acetone solution was applied to the right ear for induction. One hour after induction, each preparation (10 mg) was applied to the right auricle, 24 hours after induction, the left and right auricles were punched, the weight of the punched auricle was measured, and edema was calculated using the following formula: The rate was calculated.

  The results are shown in FIG. 1, and each composition of the example has a markedly strong ear edema rate compared to the composition of Comparative Example 1 which is a placebo, and is equivalent to that of Comparative Example 2 which is a commercial preparation. Since it was a somewhat strong result, it turns out that each composition of an Example has the outstanding pharmacological action.

[Test Example 5] Skin cumulative irritation test The composition of Example 6 was subjected to a skin cumulative irritation test using male rabbits.
The preparation (100 mg) was applied to healthy rabbit skin (2.5 cm × 2.5 cm), and after 6 hours had elapsed from the application, the preparation was wiped off with warm water using absorbent cotton. The skin reaction was observed about 23 hours after application. This operation was performed for 7 consecutive days, and the scores for each day are shown in Table 5.
Skin reaction was evaluated according to the criteria of Draize, JH (Appraisal of the safety of chemicals in foods, drugs and cosmetics, The Association of Food and Drug Officials of the United States, Topeka, Kansas, 46-59, 1965). It was.
Although the result was shown in Table 5, it was determined to be a weak stimulant, and there is no problem in using it as an external preparation.

It is a figure which shows the result of a pharmacological test.

Claims (8)

A pharmaceutical composition of the liquid crystal emulsion type containing Shikurosupori down,
0.01-1% by weight of cyclosporine,
0.1-5% by weight of a lipophilic nonionic surfactant selected from glyceryl monostearate and tetraglyceryl monostearate,
0.1 to 5% by weight of a hydrophilic nonionic surfactant selected from polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene hydrogenated castor oil 60,
0.5 to 10% by weight of oil selected from squalane, glycerin triisooctanoate and octyldodecanol,
Fatty acids that do not dissolve in the oil, 0.1 to 1% by weight of saturated and linear fatty acids having 16 to 22 carbon atoms that are solid at room temperature
A solid higher alcohol that does not dissolve in the oil, 0.1 to 10% by weight of a saturated, straight-chain alcohol having 16 to 22 carbon atoms that is solid at room temperature, and
1 to 50% by weight of a water-soluble polyhydric alcohol that is immiscible with the oil, the water-soluble polyhydric alcohol selected from 1,3-butylene glycol and glycerin
A liquid crystal emulsified pharmaceutical composition. The liquid crystal emulsified pharmaceutical composition according to claim 1, wherein the fatty acid is selected from palmitic acid, stearic acid, and behenic acid. The liquid crystal emulsified pharmaceutical composition according to claim 1 or 2, wherein the solid higher alcohol is selected from cetanol, cetostearyl alcohol, stearyl alcohol and behenyl alcohol. The liquid crystal emulsified pharmaceutical composition according to any one of claims 1 to 3, wherein the fatty acid is behenic acid. The liquid crystal emulsified pharmaceutical composition according to any one of claims 1 to 4, wherein the solid higher alcohol is selected from cetostearyl alcohol and behenyl alcohol. The liquid crystal emulsified pharmaceutical composition according to any one of claims 1 to 5, further comprising 0.05 to 0.5% by weight of an emulsion stabilizer selected from L-arginine, glycine and sodium N-acyl-L-glutamate. . The liquid crystal emulsified pharmaceutical composition according to any one of claims 1 to 6, comprising only an oil selected from squalane, glycerin triisooctanoate and octyldodecanol as the oil. As a surfactant,
A lipophilic nonionic surfactant selected from glyceryl monostearate and tetraglyceryl monostearate, and
Hydrophilic nonionic surfactant selected from polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene hydrogenated castor oil 60
The liquid-crystal emulsion type pharmaceutical composition of any one of Claim 1 thru | or 7 containing only this.