JPH07278007A - Emulsion composition containing cyclosporin - Google Patents

Abstract

PURPOSE:To obtain an emulsion composition which has excellent stability, even when cyclosporin is formulated in an increased concentration as an external preparation. CONSTITUTION:The oil-in-water type emulsion composition containing cyclosporin comprises (A) 0.1-10wt.% of cyclosporin, (B) 2-50wt.% of a polycarboxylic acid polyalkyl ester which is liquid at room temperature, for example, dibutyl phthalate, diethyl sebacate, isopropyl azelate, or isobutyl adipate, (C) 1/50-1 time weight (based on the total weight of A+B) of an oil which is liquid at room temperature and has 0-0.25 I.O.B., such as olive oil, oleyl oleate, squalane, liquid paraffin, silicone oil and (D) 0.5 to 50wt.% of a surfactant. When an oil which is liquid at room temperature and has an I.O.B. from 0.5 to 85 is added in a small amount (0.1wt.% based on the total amount of A+B), an increased amount of cyclosporin can be solubilized.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cyclosporin-containing emulsion composition which is excellent in stability and transdermal absorbability, has no skin irritation and can contain cyclosporin in a high concentration.
Cyclosporin is a cyclic peptide consisting of 11 amino acids, and many natural or synthetic so-called "cyclosporins" known as AI and the like have been known so far. The "cyclosporin" in the present invention includes each of these peptides and a mixture of each peptide.

[0002]

Cyclosporine has been used as an immunosuppressant or anti-inflammatory agent for organ transplantation, for example, for transplantation of many atypical organs such as heart, lung, liver, kidney, pancreas, skin and cornea. Along with it, it is widely used for autoimmune diseases such as severe psoriasis, Pechet's disease, Graves' disease, post uveitis, Crohn's disease, diabetes, ulcerative colitis, myasthenia gravis, rheumatoid arthritis, etc. Efficacy has been reported.

Especially for psoriasis, the effectiveness in oral administration has been confirmed so far, and many clinical results are now reported (for example, British Jounal of Dcrmatology. V.
ol.122, suppl.36.1990). However, in the case of oral administration, many side effects such as nephrotoxicity and hepatotoxicity peculiar to cyclosporine have been reported, and the bioavailability at oral administration is as low as about 30%, and it may vary depending on the individual. It is difficult to set the dose, and there are many problems in the treatment by oral administration.

[0004] Against this background, a therapeutic method in which it is directly applied to the psoriasis site and percutaneously absorbed is attempted, and development of an effective external preparation without the above-mentioned side effects is desired. However, since cyclosporin is a drug characterized by having a large molecular weight and high hydrophobicity, it can be prepared by dispersing it in a lipophilic base such as petrolatum or liquid paraffin or a hydrophilic base such as polyethylene glycol. , Transdermal absorption of cyclosporine is not desired.

Further, cyclosporine dissolves well in methanol, ethanol, acetone, ether, chloroform, etc., so that topical administration by a preparation dissolved in alcohols, especially ethanol can be considered. Since the crystals of (3) easily precipitate, the drug cannot be blended in a high concentration, and a sufficient amount for treatment cannot be percutaneously absorbed. Further, in the case of psoriasis or atopic dermatitis, which requires long-term continuous use, the alcohol-containing preparation is not necessarily a preferable preparation from the viewpoint of skin safety.

As a prior art relating to a cyclosporin-containing composition, JP-A-2-49733 discloses an emulsion formulation containing a medium-chain fatty acid diglyceride or monoglyceride, and JP-A-2-121929 discloses a hydrophilic component and a medium chain. Emulsified composition containing fatty acid triglyceride and surfactant, pharmaceutical composition comprising fatty acid saccharide monoester and diluent in JP-A-2-235817, fatty acid triglyceride and glycerin fatty acid moiety in JP-A-2-255623. A pharmaceutical composition comprising an ester and the like and JP-A-2-290809 describe an emulsion composition comprising a medium chain fatty acid triglyceride, a vegetable oil, a surfactant and the like.

However, even with these techniques, it is impossible to mix cyclosporin in a high concentration, and the stability of the preparation is insufficient, and therefore these have not yet been put into practical use.

[0008]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to obtain an emulsified composition having excellent stability and excellent transdermal absorbability even when cyclosporin is added at a high concentration as an external preparation.

[0009]

According to the present invention, (a)
Cyclosporine, (b) polycarboxylic acid polyalkyl ester which is liquid at room temperature, (c) I.V. O. B is 0 to 0.25
A cyclosporin-containing oil-in-water emulsion composition containing an oil component that is liquid at room temperature and (d) a surfactant is provided.

The present invention will be described in detail below. The present inventors have found that by using a polycarboxylic acid polyalkyl ester as a lipophilic component, cyclosporin can be blended at a high concentration, and a cyclosporin emulsion composition that is pharmaceutically stable can be obtained. It was

The amount of cyclosporin used in the present invention is preferably 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the weight of the emulsion composition.

The polycarboxylic acid polyalkyl ester blended in the present invention need only be a liquid at room temperature. An aliphatic, araliphatic or aromatic polycarboxylic acid, which is preferably an ester having a total carbon number of 10 to 25, has two or more carboxy groups, and the carboxy groups are bonded aliphatically or aromatically, Esters with linear or branched alcohols are preferred. Incomplete esterification products can also be used in the present invention. The esters may be used alone or as a mixture of two or more kinds. The blending amount is not particularly limited as long as it dissolves cyclosporine, preferably 2 to 50% by weight, more preferably 5 to 40% by weight based on the weight of the emulsified composition.
%, Particularly preferably 5 to 30% by weight.

Specific examples of the polycarboxylic acid polyalkyl ester include adipic acid dialkyl ester having 12 to 22 carbon atoms, pimelic acid dialkyl ester having 13 to 23 carbon atoms, and 14 to 24 carbon atoms. Suberic acid dialkyl ester, total carbon number 13-21 azelaic acid dialkyl ester, total carbon number 14-22 sebacic acid dialkyl ester, total carbon number 14-24
Phthalic acid dialkyl ester (provided that these alkyl groups may be linear or branched, and the alkyl portions of the dialkyl may be the same or different).

Among these, preferred representative examples include dibutyl phthalate, diethyl phthalate, diisobutyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate, diisobutyl adipate. .

As described above, the amount of cyclosporine is preferably 0.1 to 15% by weight. If the amount of cyclosporine is small, it is easy to prepare but the pharmacological effect tends to be poor. If it is too much, a large amount of polycarboxylic acid polyalkyl ester for dissolving cyclosporine must be blended, and as a result, the polarity may become high, and the emulsion composition becomes unstable. In addition, I. O. B. When an oil content of 0 to 0.25 is added, a stable emulsion composition can be obtained even if a large amount of polycarboxylic acid polyalkyl ester is added.

The above I. O. B. The oil content of 0 to 0.25 includes triglycerides (eg olive oil, soybean oil, rapeseed oil, coconut oil, etc.), synthetic ester oils (eg oleyl oleate, isopropyl myristate, cetyl myristate, etc.), squalane, and fluid Examples include paraffin and silicone oil. Further, these oil components can be used alone or as an arbitrary mixture.

These oils preferably have a molecular weight of about 200 or more, and are preferably liquid at room temperature from the viewpoint of handling. The blending amount of these oil components is preferably 1/50 times to 1: 1 times, more preferably 1/20 times to 1/2 times the total blending amount of cyclosporine and polycarboxylic acid polyalkyl ester. If the blending amount of these oil components is too small, it is not preferable for stabilizing the emulsion composition, and on the contrary, if the blending amount is too large, crystals of cyclosporine may be precipitated.

According to the present invention, as a solubilizing agent for cyclosporin, in addition to polycarboxylic acid polyalkyl ester, I.V. O. B. It is possible to add one or more oils that are liquid at room temperature and have a value of more than 0.25 and 0.85 or less.
It is convenient to add a small amount of this oily component because the amount of polycarboxylic acid polyalkyl ester used can be greatly reduced and a large amount of cyclosporine can be dissolved.

Specific examples of these oils include crotamiton, benzyl alcohol, phenethyl alcohol, higher alcohols (eg, 2-octyldodecanol, oleyl alcohol, 2-hexyldecanol, etc.), higher fatty acids (eg, oleic acid, linole). Acid, linoleic acid, etc.), but crotamiton is particularly preferable. The blending amount of these oil components is preferably 0.1 to 10% by weight, and more preferably 0.1 to 10% by weight based on the total amount of cyclosporine and polycarboxylic acid polyalkyl ester.
It is 5 to 5% by weight. In this case, the compounding amount of the polycarboxylic acid polyalkyl ester is 5 to 30% by weight.

The I.D. O. B. (Ino
The value of "organic OrganicBalance" is "Chemical field", Vol. 11, No. 10, 719-72.
This is the ratio of the inorganic and organic values calculated according to the calculation method by Fujita shown on page 5, (1957), that is, the numerical value represented by the following formula.

I. O. B. = Σ (inorganic) / Σ (organic)

The surfactant used in the present invention is a nonionic surfactant (ester type: sorbitan fatty acid ester, glycerin fatty acid ester, decaglycerin fatty acid ester, prepylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil). Etc., ether type: polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, etc.),
Either an ionic surfactant (sodium lauryl sulfate, sodium cetyl sulfate, etc.) or an amphoteric surfactant (betaine, aminocarboxylic acid, etc.) can be used, and these can be used alone or as an arbitrary mixture. The blending amount thereof is preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, particularly preferably 1 to 7% by weight, based on the total weight of the emulsion composition. If the amount of this surfactant is small, the emulsion composition may become unstable, and if it is too large, the usability may deteriorate.

When this preparation is made into a cream preparation, it is natural to add solid higher fatty acid (eg palmitic acid, stearic acid, behenic acid etc.) or higher alcohol (eg cetyl alcohol, stearyl alcohol, behenyl alcohol etc.). it can. It is also possible to add a semi-solid oil component (eg petrolatum, hydrogenated oil, etc.). Further, it can be thickened with a water-soluble polymer to give a cream preparation. Examples of the water-soluble polymer in this case include carboxyvinyl polymer, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and the like.

These can be used alone or as an arbitrary mixture. In addition, a neutralizing agent for adjusting the pH of the preparation (eg, inorganic base such as sodium hydroxide, potassium hydroxide, aqueous ammonia, organic base such as triethylamine, triethanolamine, diisopropanolamine, etc.) can be used. . If necessary, other wetting agents (eg propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, etc.), preservatives (eg methylparaben, ethylparaben, propylparaben, benzalkonium chloride, benzethonium chloride, etc.) An oxidizing agent (for example, dibutylhydroxytoluene, ascorbic acid, d1-α-tocopherol, sodium edetate, etc.) can be added.

In the case of forming an emulsion or cream as one aspect of the present invention, water is an essential component, and its blending amount is preferably 2
It is 0 to 90% by weight.

The cyclosporin-containing preparation according to the present invention can be produced by any method known to those skilled in the art for producing an emulsion composition. For example, cyclosporin is added to polycarboxylic acid polyalkyl ester and dissolved by heating, and an oil phase is prepared by adding an oil component while gradually cooling to room temperature. On the other hand, the aqueous phase is prepared by adding a surfactant to a wetting agent, heating and dissolving it, and then adding water thereto. Next, the cyclosporin-containing emulsion composition can be obtained by emulsifying under high speed stirring while adding the oil phase to the water phase.

In the present invention, a stable emulsified composition can be obtained regardless of the particle size of the emulsion, so that the emulsification can be carried out by a normal homomixer. However, Ultrasonic homogenizer (made by Ultrasonic, Inc. in the United States)
Such as ultrasonic emulsifier, Polytron emulsifier (POLYTRON registered trademark TypePT4 manufactured by Kinematica, Switzerland)
It can also be produced using a high-speed rotary emulsifying machine such as 5/50). Further, in order to obtain an emulsified composition having a fine emulsion particle size, Manton Gaulin homogenizer (Type 15M-8TA manufactured by Manton Gaulin Co., USA) or Microfluidizer (Ty manufactured by Microfluidizer USA) is used.
A pressure emulsifier such as pe110T) can be used.

[0028]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited to these examples. In addition, "%" shows "weight%" unless there is particular notice.

Example 1 (Formulation) Component % (1) Cyclosporine 1 (2) Diisopropyl adipate 5 (3) Dibutyl sebacate 5 (4) Olive oil 2 (5) Liquid paraffin 3 (6) P. O. E. (20) Sorbitan monostearate 2.8 (7) Monoglyceryl stearate 2 (8) Glycerin 10 (9) Carboxyvinyl polymer 0.2 (10) Diisopropanolamine Appropriate amount (11) Preservative Appropriate amount (12) Purified water Residual total 100%

(Production method) Component (1) is replaced with components (2), (3)
Was added and dissolved by heating, and the components (4) and (5) were added to this to prepare an oil phase. On the other hand, the components (6), (7), (8)
Part of the component (12) was added to and dissolved by heating. The oil phase previously prepared was added to this, and ultrasonic emulsification was carried out to prepare an emulsion. Further, the components (9) and (11) were dissolved in the rest of the component (12) with stirring. To this, the component (10) was added to make the pH neutral, and the emulsion prepared above was added and stirred until it was even, to obtain an emulsion preparation. The emulsion particle size of this preparation was 1 μm or less, and cyclosporin crystals were not observed.

Example 2 (Formulation) Component % (1) Cyclosporin 5 (2) Crotamiton 2 (3) Diethyl sebacate 15 (4) Squalane 4 (5) P. O. E. (55) Monostearate 2 (6) Decaglycerin monooleate 1 (7) 1,3-Butylene glycol 8 (8) Carboxyvinyl polymer 0.8 (9) Diisopropanolamine proper amount (10) Preservative proper amount (11) Purified water residual total 100%

(Production method) Component (1) is replaced with components (2), (3)
Was dissolved by heating, and the component (4) was added thereto to prepare an oil phase. On the other hand, a part of the component (11) was added to the components (5), (6) and (7) and dissolved by heating. The oil phase prepared previously was added to this, and it emulsified with the homomixer, and the emulsion was prepared. Further, the components (8) and (10) were dissolved in the rest of the component (11) with stirring. The component (9) was added thereto to adjust the pH to neutral, and the emulsion prepared above was added and stirred until it was even, to obtain a cream preparation. The emulsion particle size of this preparation is 1 μm
Below, and no crystals of cyclosporin were observed.

Example 3 (Formulation) Component % (1) Cyclosporine 5 (2) Crotamiton 2 (3) Diethyl sebacate 15 (4) Squalane 4 (5) P. O. E. (55) Monostearate 2 (6) Decaglycerin monooleate 1 (7) 1,3-butylene glycol 8 (8) Stearyl alcohol 1.5 (9) Cetyl alcohol 3.5 (10) Stearic acid 1.5 ( 11) Panacet 875 1 (12) Ethylparaben Appropriate amount (13) Tenos MG 3 (14) Sodium cetyl sulfate 0.2 (15) Purified water Residual total 100%

(Production method) Component (1) is replaced with components (2), (3)
Was dissolved by heating, and the component (4) was added thereto to prepare an oil phase. On the other hand, a part of the component (15) was added to the components (5), (6) and (7) and dissolved by heating. The oil phase previously prepared was added to this and emulsified with a homomixer to prepare an emulsion (component A). Components (8), (9), (10), (1
An oil phase was prepared by heating and dissolving 1), (12) and (13). Further, the component (14) was dissolved in the rest of the component (15), the above oil phase was added, and the mixture was emulsified with a homogenizer to prepare an emulsion (component B). Furthermore, the component A was added to the component B, mixed with stirring, and cooled to obtain a cream preparation. The emulsion particle size of this preparation was 1 μm or less, and cyclosporin crystals were not observed.

[0035] Example 4 (Formulation) Ingredient% (1) cyclosporin 10 (2) Diethyl sebacate 30 (3) Oleic acid 5 (4) Liquid paraffin 7 (5) P. O. E. (60) hydrogenated castor oil 2 (6) P. O. E. (25) Cetyl ether 1.5 (7) Propylene glycol 10 (8) Carboxyvinyl polymer 0.8 (9) Potassium hydroxide proper amount (10) Preservative proper amount (11) Purified water residual total 100%

(Production method) Component (1) was added to component (2) and dissolved by heating, and then components (3) and (4) were added thereto to prepare an oil phase. On the other hand, a part of the component (11) was added to the components (5), (6) and (7) and dissolved by heating. The oil phase prepared above was added thereto, and the mixture was emulsified with a homomixer and further emulsified under pressure using a Manton Gaulin homogenizer to prepare an emulsion. Furthermore, the component (8) is dissolved in the rest of the component (11) with stirring, and the component (9) is added thereto to make the pH neutral, and this is added to the emulsion prepared above, and stirred until uniform. To obtain a cream formulation. The emulsion particle size of this preparation is 1
It was less than μm, and no crystals of cyclosporin were observed.

[0037] Example 5 (Formulation) Ingredient% (1) cyclosporin 5 (2) dibutyl phthalate 20 (3) oleyl oleate 5 (4) Liquid paraffin 5 (5) P. O. E. (45) Stearate 5 (6) Potassium stearate 0.5 (7) Propylene glycol 8 (8) Glycerin 2 (9) Preservative proper amount (10) Purified water residual total 100%

(Production method) Component (1) was added to component (2) and dissolved by heating, and then components (3) and (4) were added to prepare an oil phase. On the other hand, the components (5), (6), (7), (8)
Part of the component (10) was added to and dissolved by heating. The oil phase prepared above was added to this and emulsified with a homomixer, and further emulsified under pressure using a Manton Gaulin homogenizer to prepare an emulsion. Furthermore, the component (9) is dissolved in the rest of the component (10) with stirring, and this is added to the emulsion prepared above,
The mixture was stirred until it became even, to obtain an emulsion. The emulsion particle size of this preparation was 1 μm or less, and cyclosporin crystals were not observed.

Example 6 (Formulation) Component % (1) Cyclosporine 3 (2) Dibutyl adipate 20 (3) Isopropyl myristate 2 (4) Squalane 3 (5) Decaglycerin monostearate 3 (6) Hydrogenation Lecithin 0.5 (7) 1,3-butylene glycol 3 (8) Glycerin 12 (9) Preservative proper amount (10) Purified water residual total 100%

(Production method) Component (1) was added to component (2) and dissolved by heating, and then components (3) and (4) were added thereto to prepare an oil phase. On the other hand, the components (5), (6), (7), (8)
Part of the component (10) is added to and dissolved by heating, and the oil phase prepared above is added to this and emulsified with a polytron using an emulsifier,
An emulsion was prepared. Furthermore, the component (9) is added to the component (10)
Was dissolved by stirring in the rest of the mixture, and this was added to the previously prepared emulsion, and the mixture was stirred until the mixture became even, to obtain an emulsion. The emulsion particle size of this preparation was 1 μm or less, and cyclosporin crystals were not observed.

Example 7 (Formulation) Component % (1) Cyclosporin 5 (2) Crotamiton 2 (3) Dibutyl phthalate 8 (4) Oleic acid 2 (5) Squalane 9 (6) Propylene glycol 2 (7) P ． O. E. (55) Monostearate 1.5 (8) Dodecyldimethylamine oxide 1 (9) Sodium cetyl sulfate 0.2 (10) Cetyl alcohol 2.5 (11) Stearyl alcohol 4 (12) Behenic acid 1 (13) White Vaseline 8 (14) Glycerin monostearate 3 (15) Carboxyvinyl polymer Appropriate amount (16) Glycerin Appropriate amount (17) Sodium edetate Appropriate amount (18) Sodium hydroxide Appropriate amount (19) Preservative Appropriate amount (20) Purified water Residual total 100 %

(Production method) Component (1) is replaced with components (2) and (3)
Was dissolved in the solution under heating, and a part of the components (4) and (5) was added thereto to prepare an oil phase. On the other hand, components (6) to (9)
Part of (20) was added to and dissolved by heating. The oil phase previously prepared was added to this and emulsified with a homomixer to prepare an emulsion (component A). Residue of component (5), (10) to (1
4) was dissolved by heating to prepare an oil phase. In addition, the component (1
After dissolving 5) to (19) in the rest of (20), the above oil phase was added and emulsified with a homogenizer to obtain an emulsion (component B).
Was prepared. Further, component A is added to component B, and they are mixed by stirring
Cooled to obtain a cream formulation. The emulsion particle size of this preparation is 1
It was less than μm, and no crystals of cyclosporin were observed.

Reference Example 1 (Prescription) Component % (1) Cyclosporin 5 (2) Ethyl alcohol 10 (3) Olive oil 73 (4) P. O. E. (5) Glyceryl monostearate 5 (5) Aloedir 200 7 Total 100%

(Production method) The component (3) is added to the component (4), dissolved by heating, and cooled. To this, a solution prepared by adding and dissolving the component (1) to the component (2) was added, and the component (5) was further added and mixed with stirring to obtain a gel preparation.

Experimental Example 1 (Thermal stability test) About 5 g of the cream preparation of Example 2 was filled in a 20 ml glass container, sealed, and then stored in a constant temperature bath at room temperature and 40 ° C. to change appearance, crystal precipitation and drug content. Considered the changes. The product of Reference Example 1 was used as the target product, and the content was quantified by liquid chromatography. The results are shown in Table 1.

[0046]

[Table 1]

As a result, it was found that the product of the present invention did not precipitate crystals for a long period of time and was excellent in thermal stability. On the other hand, in the gel preparation of Reference Example 1, crystals were immediately precipitated by evaporation of alcohol.

Experimental Example 2 (Drug Permeability Test) With respect to the cream preparation of Example 2 and the gel preparation of Reference Example 1, the skin permeability of cyclosporine was examined using a snake skin. A vertical Franz cell was used for the device, and the quantification was performed by liquid chromatography. The result is shown in FIG. From this result, it was confirmed that the skin permeation from the product of the present invention was excellent as compared with the conventional preparation dissolved in alcohol.

Experimental Example 3 (Transdermal Absorption Test) C3H / Crj hairless mouse (6 weeks old, body weight: about 25)
g) was applied to 5 groups per group, and about 1.2 g of the cream preparation of Example 3 and the gel preparation of Reference Example 1 was applied to the back, covered with gauze and fixed with tape. After application, blood was collected from the posterior vena cava at the following times to measure the drug concentration in blood.
The quantification was performed by the radioimmunoassay method. The result is shown in FIG.

Experimental Example 4 (Pharmacological effect test) Dinitrochlorobenzene (DNCB) -sensitized guinea pigs (6 weeks old, body weight: about 350 g) were used as 5 animals per group, and immediately after induction of sensitization, the cream preparation of Example 3 and the reference example. The contact sensitization property was obtained by applying about 1.0 g each of the gel preparation of Example 1 and a total of 4 preparations of Example 3 and Reference Example 1 containing no cyclosporine as a placebo once to the same site coated with DNCB. The inhibitory effect was evaluated.
The evaluation was based on the following criteria.

[Evaluation Criteria for Positive Reaction] (Formation of erythema and crust) No erythema 0 0 Slight erythema 1 Clear erythema 2 Medium erythema 3 Severe erythema with slight scabs 4 (Edema formation) No edema 0 Slight edema 1 Medium edema 2 Strong edema 3

FIG. 3 shows the result of the average score of the positive reaction, and Table 2 shows the result of the positive rate when positive erythema was recognized.

[0053]

[Table 2]

As is clear from the above results, the cream preparation of the present invention showed a stronger inhibitory reaction against contact sensitization than the gel preparation of Reference Example. This proves the excellent transdermal absorbability of the present invention.

[0055]

The cyclosporin-containing oil-in-water emulsion composition according to the present invention can contain cyclosporine in a high concentration, has excellent stability over time, exhibits good transdermal absorbability, and has no skin irritation. It has the excellent property of being a thing.

[Brief description of drawings]

FIG. 1 is a graph showing drug permeability of a cream preparation of Example 2 and a gel preparation of Reference Example 1.

FIG. 2 is a graph showing the transdermal absorbability of the cream preparation of Example 3 and the gel preparation of Reference Example 1.

FIG. 3 is a graph showing the effect of suppressing contact sensitization on the cream preparation of Example 3, the gel preparation of Reference Example 1, and the cyclosporin-free target preparation.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 9/107 S E 47/14 E J G C07K 7/52 8318-4H // (A61K 47/14 47: 44) A61K 37/02 ADA

Claims (9)

[Claims] 1. (a) Cyclosporine, (b) polycarboxylic acid polyalkyl ester which is liquid at room temperature, (c) I.D.
O. B. Oil content at room temperature of 0 to 0.25 and (d)
A cyclosporin-containing oil-in-water emulsified composition comprising a surfactant. 2. The emulsified composition according to claim 1, wherein the compounding amount of cyclosporine is 0.1 to 10% by weight based on the total weight of the emulsified composition. 3. The emulsified composition according to claim 1, wherein the amount of the polycarboxylic acid polyalkyl ester is 2 to 50% by weight based on the total weight of the emulsified composition. 4. The oil content is 1/5 based on the total amount of cyclosporine and polycarboxylic acid polyalkyl ester.
The emulsion composition according to claim 1, wherein the amount is 0 to 1 times. 5. O. B. The emulsified composition according to any one of claims 1 to 4, further comprising an oil component at a room temperature of more than 0.25 and not more than 0.85. 6. The emulsified composition according to any one of claims 1 to 5, wherein the content of the surfactant is 0.5 to 15% by weight based on the total amount of the emulsified composition. 7. The polycarboxylic acid polyalkyl ester is at least one selected from dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, diisopropyl azelate, diisopropyl adipate, dibutyl adipate and diisobutyl adipate. The emulsified composition according to any one of claims 1 to 6. 8. I. O. B. Wherein at least one of the oil components which is liquid at normal temperature is 0 to 0.25 is at least one selected from olive oil, soybean oil, oleyl oleate, diisopropyl myristate, cetyl myristate, squalane, liquid paraffin and silicone oil. The emulsified composition according to any one of 7 above. 9. I. O. B. Is at least one kind selected from crotamiton, oleic acid, oleyl alcohol, benzyl alcohol and phenethyl alcohol, and the liquid oil content at room temperature of 0.25 to 0.85 is at least one kind. Emulsified composition.