WO2000041702A1 - External steroid preparation - Google Patents

Abstract

An external steroid preparation comprising a 21-alkoxysteroid compound represented by formula (I), propylene carbonate, and a polyoxyethylene/hardened castor oil. In said formula R1 represents C¿1-4? alkyl or methylthiomethyl; R?2¿ represents C¿2-7? alkanoyl; and the wavy line indicates α- or β-coordination.

Description

 Description Steroid external preparation Technical field

 The present invention relates to a steroid external preparation containing a 21-alkoxy sulfide compound having a specific structure as an active ingredient, and more specifically, a 21-alkoxy compound having excellent dispersibility in a base and emulsion stability. It relates to topical steroid preparations. Further, the present invention relates to a steroid ointment. Background art

Conventionally, various corticosteroids have been used as corticosteroids for the purpose of preventing, treating, and treating inflammatory skin diseases, asthma allergic diseases, and rheumatic diseases. Such steroids have been variously developed according to the target disease. For example, Japanese Patent Application Laid-Open No. 3-68039 discloses a steroid having a strong anti-inflammatory effect upon topical administration. Disclosed are 21-alkoxy sulfide compounds which are sulfide compounds. On the other hand, methods for topical administration of steroid compounds include ointments, aqueous gels, mouthwashes, creams, powders, sprays, and tapes. Here, a steroid external preparation using an oily base is frequently used when the skin is wet or dry, and has the advantage of less irritation to the skin because white vaseline or the like is used as the base. In addition, a cream using an emulsion base is often used when the lesion is moist on the skin, and has the advantage of having a beautiful appearance and being washable. However, the choice of these topical steroid preparations depends not only on the above-mentioned safety and properties of the diseased site, but also on the view that the active ingredient exhibits its pharmacological action most effectively and is stable for a long period of time. Needed from the point.

 For example, since lower alcohols are excellent in volatility, if the lower alcohol mixed in the base is volatilized after use, the active ingredient is precipitated as crystals, which may hinder transdermal absorption of the medicinal ingredient. On the other hand, in order to improve the transdermal absorption of a medicinal ingredient by blending a transdermal absorption agent, it is necessary to add a large amount of a transdermal absorption enhancer, and the safety of the transdermal absorption enhancer such as irritation to the skin There is a problem from the aspect. In general, it is preferable to dissolve the active ingredient in the base in order to obtain high efficacy, but in order to ensure the release of the active ingredient from the base, a solubility that does not affect the drug release is required. That is, a balance between drug release and solubility in the base is required.

 Here, 21 monoalkoxy steroid compounds are used for various clinical skin diseases such as acute eczema, chronic eczema, seborrheic eczema, atopic dermatitis, pediatric eczema, contact dermatitis, psoriasis vulgaris, etc. Can be used for treatment. For use in such applications, it is preferable to use it as an external application agent, and it is preferable to use it as an ointment, solution, emulsion or the like.

 However, since 21-alkoxy sulfide compounds are hardly soluble, it is difficult to make them soluble in order to exhibit their pharmacological effects effectively. Disclosure of the invention

 As a result of intensive studies on the 21-alkoxysteroid compound and various ointment bases, the present inventor found that propylene carbonate was blended with polyoxyethylene hydrogenated castor oil as a surfactant. The present inventors have found that an ointment having extremely excellent solubility and drug release properties can be obtained, and have completed the present invention.

 That is, the present invention provides the following (1) to (8).

(1) A 21-alkoxy sulfide compound represented by the formula (I), An external preparation for steroid containing propylene carbonate and polyoxyethylene hydrogenated castor oil.

(式中、 R ¹は炭素数 1〜 4個のアルキル基またはメチルチオメチル 基を示し、 R²は、 炭素数 2〜 7個のアルカノィル基を示し、 波線は、 ひ配位または/?配位であることを示す。 ）

(Wherein, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a methylthiomethyl group, R ² represents an alkanol group having 2 to 7 carbon atoms, and wavy lines represent Is shown.)

 (2) The external preparation for steroids according to the above (1), wherein the polyoxyethylene hydrogenated castor oil is obtained by repeating oxyethylene units by 10 to 60.

 (3) The steroid external preparation according to the above (1) or (2), wherein the content of the 21-alkoxysteroid compound is 0.01 to 1% by mass.

 (4) Any one of the above (1) to (3), wherein the propylene carbonate is contained in an amount of 1 to 5% by mass and the polyoxyethylene hydrogenated castor oil is contained in an amount of 0.01 to 3% by mass. The steroid external preparation according to any one of the above.

 (5) A steroid ointment containing the steroid external preparation according to (1) to (4).

(6) A 21-alkoxy sulfide compound represented by the following formula (I) is dissolved in a liquid base containing propylene carbonate at a temperature of 40 to 100 ° C, and then cured with polyoxyethylene. Solid base dissolved with castor oil Ointment obtained by mixing with an ointment base containing

(7) The content of the 21-alkoxy sulfide compound is 0.01 to 1% by mass in the ointment, the propylene carbonate is 1 to 5% by mass in the ointment, and The steroid ointment according to the above (6), wherein the ethylene-hardened castor oil is 0.01 to 3% by mass in the ointment.

 (8) The steroid ointment according to (7), wherein the 21-alkoxysteroid compound is amelomethasone represented by the formula (II).

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention, a hardly soluble 21-alkoxy sulfide compound is used as a soluble form. As a result, it is a steroid ointment that can provide excellent local anti-inflammatory activity even with a small amount. As a result of examining various bases as dissolving agents for such hardly soluble compounds, it was found that propylene carbonate can be an extremely excellent dissolving agent, and that various surfactants can be used from the viewpoint of emulsion stability in an ointment base. As a result of the investigation, it was found that when emulsified polyoxyethylene castor oil was used as a surfactant, excellent emulsion stability was obtained. In addition, it was found that the combination of the two not only provides excellent emulsion stability, but also provides rapid drug efficacy and sustained drug efficacy. Such an effect is an excellent effect that cannot be obtained by simply blending an ointment base. Moreover, even if the amount of the compound added to the ointment base is small, a sufficient local anti-inflammatory effect can be obtained, so that the amount of the compound can be reduced. Hereinafter, the present invention will be described in detail.

(1) 21 -Alkoxysteroid compound

The 21-alkoxy steroid compound of the present invention is a compound represented by the above formula (I). In the formula (I), examples of the alkyl group for R ¹ include a methyl group, an ethyl group, and a propyl group. Examples of the alkanoyl group for R ² include an alkanoyl group having a linear or branched alkyl group, such as an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, and an isovaleryl group. R ² is particularly preferably an alkanoyl group having 2 to 4 carbon atoms. As the 21-alkoxy steroid compound used in the present invention, a compound in which R ² is an acetyl group, a propionyl group or a butyryl group is preferable. This is because it has a particularly excellent local anti-inflammatory effect as compared with related steroid compounds such as mesasone 21-methoxide and beta-methasone 17-valerate. Particularly, as shown in the above (II), R ¹ is a methyl group, and R ² is an acetyl group Compounds (hereinafter, this compound is referred to as “amelomezone”) are preferred. The reason is that the vasoconstriction is mild and can be maintained for a long period of time, and excellent vasoconstriction is exhibited even when a diluted ointment is prepared.

 The method for producing the above 21-alkoxy sulfide compound is not particularly limited, and for example, it can be produced by the method described in Japanese Patent Publication No. 3-68039.

(2) Ointment base

 As the ointment base which can be used for the steroid external preparation and the steroid ointment of the present invention, a liquid base component and a solid base component can be used: (a) Liquid base component

 In the present specification, the liquid base component refers to a base liquid at room temperature. In the present invention, a liquid base component can be used as an ointment base component, and examples thereof include propylene carbonate. The present invention is particularly characterized in that propylene carbonate is used. According to propylene carbonate, the hardly soluble 21-alkoxysulfide compound can be easily dissolved. In addition, it is excellent as an ointment base even at the L 'point, which has little irritation to the skin. Furthermore, when propylene carbonate is used as an ointment base for a 21-alkoxysteroid compound, it is excellent in releasing 21-alkoxycysteloid compounds from the base and extremely excellent as an ointment base for topical anti-inflammatory agents. It is.

In the present invention, it is essential that propylene carbonate be blended as an ointment base component, but one or more other liquid bases may be blended as long as the properties of the ointment are not lost. Good. Among these combinations, a combination of propylene glycol and propylene carbonate is preferable, and a mixture of liquid paraffin is also preferable. Pro pyrengli This is because coal has excellent affinity with propylene carbonate and has a moisturizing effect.

 (b) Solid base component

 In the present specification, the solid base component refers to a base that is solid at normal temperature.

 The solid base that can be used in the present invention is not particularly limited as long as it is solid at normal temperature. For example, solid triglyceride, solid fatty acid ester, solid hydrocarbon, and the like can be used. Triglycerides as solid bases include cocoa butter, palm fat, palm kernel oil, mokurou, coconut oil, beef tallow, lard, hydrogenated oil, hydrogenated castor oil, lanolin fatty acid triglyceride, etc. No. Fatty acid esters as solid bases include beeswax, carnauba wax, whale wax, lanolin, hydrogenated lanolin, hard lanolin, candelilla wax, ceresin and the like. Examples of the hydrocarbon as a solid base include white petrolatum, yellow petrolatum, paraffin, solid paraffin, ozokerite, ceresin, microcrystalline wax, polyethylene powder, and the like. There is no problem if it is used for cosmetics. In the present invention, these solid bases are blended together with the liquid base. In the present invention, it is preferable to use white petrolatum, solid paraffin, and ceresin as the solid base.

 (c) Surfactant

The steroid ointment of the present invention is characterized by containing polyoxyethylene hydrogenated castor oil as a surfactant. This is because it is particularly excellent in affinity with propylene carbonate. Therefore, even when a propylene carbonate solution in which a sparingly soluble 21-alkoxy sulfide compound is dissolved is mixed with a solid base, the polyoxyethylene-hardened castor oil exhibits an extremely excellent emulsifying action, This is because a steroid ointment having excellent emulsion stability can be obtained. In the present invention, polyoxyethylene cured castor Among these oils, those which repeat oxyethylene units by 10 to 60 are preferable, and those which repeat oxyethylene units by 20 to 50, especially 20 are particularly preferable. In this range, particularly excellent emulsion stability can be obtained, and the release of the active ingredient 21-alkoxy steroid compound from the steroid ointment is extremely efficiently performed. That is, by using such polyoxyethylene hydrogenated castor oil, it is expected that the 21-alkoxy steroid will quickly and continuously exert its medicinal effect.

 In the present invention, in addition to polyoxyethylene hydrogenated castor oil, one or more other surfactants can be used in combination as the surfactant. For example, examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, and polyoxyethylene fatty acid ester. Examples of the anionic surfactant include a linear or branched alkylbenzene sulfonate, a linear or branched alkyl or alkenyl ether sulfate, an alkyl or alkenyl sulfate having an alkyl group or a alkenyl group, and an alkyl. There is a phosphoric acid monomer- or diester-type surfactant containing a group or an alkenyl group. Further, examples of the amphoteric surfactant include imidazoline-based amphoteric surfactants having an alkyl group, an alkenyl group, or an acyl group, a carbobenzoin-based surfactant, an amide-based surfactant, and a sulfobetaine-based surfactant. And amphoteric surfactants such as hydroxysulfobetaine and amidesulfobetaine.

(3) Steroid external preparation

The topical steroid formulation of the present invention is characterized by containing a 21-alkoxy sulfide compound represented by the above formula (I), propylene carbonate and polyoxyethylene hydrogenated castor oil. Dosage forms obtained using steroid external preparations include ointments, aqueous gel ointments, lotions, There are creams, powders, sprays, tapes and the like. In the present invention, among these, ointments, lotions and creams are preferred, and ointments are particularly preferred. In the case of ointments, lotions and creams, propylene carbonate and hardened castor oil of polyoxyethylene make the hardly soluble 21-alkoxysteride compounds soluble. This makes it possible to provide a steroid external preparation which rapidly exerts the pharmacological action of the 21-alkoxysteride compound and has excellent stability. (4) Steroid ointment

 In the present invention, an ointment can be prepared using the above-mentioned steroid external preparation. The steroid ointment of the present invention is characterized in that propylene carbonate and polyoxyethylene hydrogenated castor oil are contained in a solid base, and the propylene carbonate is contained in the ointment in an amount of 1 to 5% by mass. It is preferable that the content is 1.5 to 3.5% by mass. The ointment preferably contains 0.01% to 3% by mass of polyoxyethylene hydrogenated castor oil, and more preferably 0.05% to 2% by mass. If both are present in this range, excellent emulsification stability of the 21-alkoxysulfide compound in the base can be ensured.

Further, the 21-alkoxysteroid compound is preferably contained in the ointment in an amount of 0.01 to 1% by mass, more preferably 0.05 to 0.5% by mass. The 21-alkoxy steroid compound used in the present invention has an excellent local anti-inflammatory action, and has an ointment in combination with propylene carbonate, polyoxyethylene hydrogenated castor oil and a solid ointment base. This is because release from the base is easy, and an extremely excellent local anti-inflammatory action can be obtained in the above range. There is no particular limitation on the method for preparing such a stade ointment. To prepare a dissolvable steroid ointment, a 21-alkoxy cysteine compound represented by the above formula (I) is used. A solid base dissolved in a liquid base containing propylene carbonate at a temperature of 40 to 100 ° C, more preferably at a temperature of 40 to 80 ° C, and then dissolved with polyoxyethylene hydrogenated castor oil It is preferable to mix it with an ointment base containing At this time, one or more other liquid bases described above may be mixed with the propylene carbonate. An example of such a liquid base is propylene glycol. The amount of propylene glycol to be used is not particularly limited. However, when it is added, the amount of propylene is 0.1 to 20 parts by mass, more preferably 0.5 to 10 parts by mass, per 1 part by mass of propylene. It is preferred to mix in the range of parts. This is because the addition of propylene glycol can increase the content of the liquid base and easily adjust the softness of the ointment base.

 In the present invention, a mixture of the obtained 21-alkoxy sulfide compound and a liquid base containing at least propylene carbonate is then heated and mixed with a dissolved solid base. At this time, polyoxyethylene hydrogenated castor oil is added. This is because the polyoxyethylene hydrogenated castor oil acts as an emulsifier, and the soluble 21-alkoxysteroid compound can be easily and uniformly emulsified in the ointment base.

In the present invention, the hardly soluble 21-alkoxysteroid compound can be used as a soluble steroid ointment. Dissolved in a liquid base containing propylene carbonate at ~ 100 ° C, and then mixed with an ointment base containing a solid base dissolved with polyoxyethylene hydrogenated castor oil It can be said to be a method for solubilizing 2, 21-alkoxysteroid compounds. As the steroid ointment prepared by the above-mentioned preparation method, the content of the 21-alkoxy systemide compound in the ointment is 0.01 to 1% by mass, and the content of the propylene carbonate in the ointment is 1 to 1%. Preferably, 5% by mass, and 0.01% to 3% by mass of the polyoxyethylene hydrogenated castor oil in the ointment. Within this range, a stable local anti-inflammatory effect can be exerted over time when an appropriate amount is applied to the skin once or several times a day and used. Such a 21-alkoxysteroid compound is preferably amelomethasone represented by the above formula (II). The steroid ointment of the present invention may optionally contain an antioxidant, a preservative, a chelating agent, a fragrance, and the like, as necessary, in addition to the above components. The steroid ointment of the present invention may be combined with one or more antibiotics, antihistamines, bactericides, and vitamins.

 The steroid ointment of the present invention can be produced by mixing and mixing the above-mentioned base and surfactant according to a usual ointment production method.

 The steroid ointment of the present invention is used by applying an appropriate amount to the skin once or several times a day. Since the steroid ointment of the present invention exhibits a local anti-inflammatory effect that is stable over time, it can be used regardless of the site where it is used. Hereinafter, the present invention will be described specifically with reference to examples.

 (Example 1)

An ointment was prepared by mixing amelomesone with propylene carbonate, polyoxyethylene hydrogenated castor oil and the like in the amounts shown in Table 1 below. First, amelomesone was heated and dissolved in a mixture of propylene glycol and propylene carbonate at a temperature of 60 to 80 ° C in advance, and then dissolved in white petrolatum and liquid paraffin at about 80 ° C. Polyoxyethylene (20) hardened castor It was added together with the oil. The base was gradually cooled to about 32 ° C with stirring to obtain a sample. (Prescription 1)

table 1

(Example 2)

 The blending amount of the polyoxyethylene (20) hydrogenated castor oil of Example 1 was changed to 0.025 g, and an ointment was obtained in the same manner. (Prescription 2)

(Example 3)

 The blending amount of the polyoxyethylene (20) hydrogenated castor oil of Example 1 was 0 lg, and an ointment was obtained by the same production method. (Prescription 3)

(Example 4)

 The polyoxyethylene (20) hydrogenated castor oil of Example 1 was changed to polyoxyethylene (60) hydrogenated castor oil, and an ointment was obtained by the same production method (process 4).

(Example 5)

 An ointment was obtained in the same manner as in Example 4 except that the blending amount of the polyoxyethylene (60) hydrogenated castor oil was 0.1 g (formulation 5). (Comparative Example 1)

The polyoxyethylene (20) hydrogenated castor oil of Example 1 was An ointment was obtained in the same manner as above, except that the fatty acid ester was used (formulation 6).

(Comparative Example 2)

 The polyoxyethylene (20) hydrogenated castor oil of Example 1 was changed to polyethylene glycol fatty acid ester, and an ointment was obtained by the same production method (Formulation 7).

(Test Example 1: Emulsion stability test)

 An emulsion was prepared by mixing amelomezone with propylene carbonate and polyoxyethylene hydrogenated castor oil in the amounts shown in Table 2 below. First, amelomethasone was converted to propylene glycol / propylene carbonate.

(2: 3) The mixture was dissolved in advance. Next, the liquid paraffin and the polyoxyethylene (20) hydrogenated castor oil were heated and mixed, and then a propylene glycol-propylene carbonate mixed solution (mixing ratio of 2: 3) was added, followed by sufficient stirring to obtain a sample. This is Test Solution 1. This was stirred for a certain period of time with a mixer to obtain a uniform emulsified emulsion, and then allowed to stand at room temperature. The degree of separation after 30 minutes and 60 minutes and 1 day was visually observed over time in a test tube. The sample volume in the test tube was 10 m 1. Table 3 shows the results.

In the same manner as above, comparative test solutions 1 to 5 were prepared from test solution 2 at the mixing ratios shown in Table 2, and a test was conducted for emulsion stability. Table 3 shows the results. Table 2

(Test Example 2: Efficacy test)

 The efficacy of the 21-alkoxy cystride compound in the ointments of Examples 1 to 5 and Comparative Examples 1 and 2 was evaluated by vasoconstriction. The above ointment was applied to the inside of the forearm of about 20 healthy men for about 4 hours, and the vasoconstriction after removal of the sample was evaluated as a paleness phenomenon.

The criteria were: no response (-), slight pallor (Sat), pallor (+), marked pallor (+ +), 1: 0, soil: 1, + : 2 points, + +: Scored as 3 points. Table 4 shows the results. Table 4

(Result)

 (1) In the present invention, by using propylene carbonate as a dissolving base, a sparingly soluble 21-alkoxy sulfide compound can be made into a soluble type. In this case, extremely excellent emulsion stability was obtained by blending polyoxyethylene hydrogenated castor oil as a surfactant.

 (2) The emulsion stability differs depending on the type of polyoxyethylene hydrogenated castor oil.

It was found that when (20) hydrogenated castor oil was blended, the most excellent emulsification stability was exhibited for propylene carbonate.

(3) From the results in Table 4, even when the amounts of the 21-alkoxysteroids, for example, amelomezon, were the same, there was a difference in the efficacy depending on the type of the surfactant. However, since the steroid ointment of the present invention uses polyoxyethylene hydrogenated castor oil as a surfactant, it exhibits an excellent vasoconstrictive action immediately after use, and has a stable drug effect up to about 12 hours after application of the sample. It turned out to play. As a result, it was found that sufficient drug efficacy can be obtained even with application once or twice a day. (4) From Table 4, it was found that among oxyethylene hydrogenated castor oils, those containing 0.025 to 0.05% by mass of polyoxyethylene (20) hydrogenated castor oil had a high vasoconstriction effect. That is, by blending propylene carbonate as a dissolving agent for amelomethasone and polyoxyethylene (20) hydrogenated castor oil as an emulsifier, a steroid ointment having good emulsion stability and high efficacy can be obtained. It turned out to be possible. Industrial applicability

 The present invention is directed to dissolving a 21-alkoxy steroid compound which has not been able to exert its pharmacological action effectively because of its poor solubility. By blending polyoxyethylene hydrogenated castor oil as a surfactant, extremely excellent emulsion stability can be obtained. As a result, a quick and effective drug effect can be obtained. Therefore, even if the amount of the compound added to the ointment base is smaller than that of the conventional product, a sufficient local anti-inflammatory effect can be obtained, and the amount of the compound can be reduced.

Claims

The scope of the claims 1. A steroid external preparation containing a 21-alkoxy steroid compound represented by the formula (I), pyrene carbonate and polyoxyethylene hydrogenated castor oil.

(Wherein, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a methylthiomethyl group, R ² represents an alkanoyl group having 2 to 7 carbon atoms, and the wavy line represents Indicates that there is.)  2. The steroid external preparation according to claim 1, wherein the polyoxyethylene hydrogenated castor oil is obtained by repeating 10 to 60 oxyethylene units.  3. The steroid external preparation according to claim 1, wherein the content of the 21-alkoxysteroid compound is 0.01 to 1% by mass.  4. The steroid according to any one of claims 1 to 3, comprising 1 to 5% by mass of the propylene carbonate and 0.01 to 3% by mass of the polyoxyethylene hydrogenated castor oil. External preparation. 5. Steroid ointment containing the steroid external preparation according to claims 1-4. 6. Dissolve the 21-alkoxy sulfide compound represented by the following formula (I) in a liquid base containing propylene carbonate at a temperature of 40 to 100 ° C, and then cure the polyoxyethylene. Steroid ointment obtained by mixing with an ointment base containing a solid base dissolved together with castor oil.

7. The content of the 21-alkoxy sulfide compound is 0.1 to 1% by mass in the ointment, the propylene carbonate is 1 to 5% by mass in the ointment, and 7. The ointment according to claim 6, wherein the ethylene-hardened castor oil is 0.01 to 3% by mass in the ointment.  8. The ointment according to claim 7, wherein the 21-alkoxy steroid compound is amelomethasone represented by the formula (II).