External composition

Abstract

To provide an external composition which contains a steroidal anti-inflammatory agent and is capable of suppressing separation.SOLUTION: An external composition contains (A) a steroidal anti-inflammatory agent and (B) a ceramide.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition containing a steroid anti-inflammatory agent and capable of suppressing separation.

Background Art

[0002] Conventionally, steroid anti-inflammatory agents such as prednisolone valerate acetate have been formulated in external compositions to impart anti-inflammatory, immunosuppressive, anti-allergic effects, etc. On the other hand, external compositions containing steroid anti-inflammatory agents tend to separate into two phases (phase separation state) over time and have the drawback of poor storage stability.

[0003] Therefore, conventionally, formulation techniques for providing excellent storage stability in external compositions containing steroid anti-inflammatory agents have been reported. For example, Patent Document 1 reports that an oil-in-multivalent alcohol type emulsion formulation obtained by gradually adding an oil phase containing prednisolone valerate acetate and a polar oil component to a phase containing a surfactant and a polyhydric alcohol is gradually added to an aqueous phase component containing diphenhydramine hydrochloride, whereby an oil-in-water type skin external pharmaceutical emulsion formulation excellent in formulation stability can be obtained. Also, Patent Document 2 reports that an oil-in-water type emulsion formulation containing a heparin-like substance and prednisolone valerate acetate can suppress separation.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] Regarding topical compositions containing steroid anti-inflammatory agents, in order to diversify formulation prescriptions and further improve storage stability, the development of new formulation prescriptions is required.

[0006] Therefore, an object of the present disclosure is to provide a topical composition containing a steroid anti-inflammatory agent that can suppress separation.

Means for Solving the Problems

[0007] As a result of intensive studies to solve the above problems, the present inventor has found that by incorporating ceramide into a topical composition containing a steroid anti-inflammatory agent, separation due to storage can be suppressed and excellent storage stability can be achieved. The present disclosure has been completed by further studies based on such findings.

[0008] That is, the present disclosure provides a topical composition in the following embodiments. Item 1. A topical composition containing (A) a steroid anti-inflammatory agent and (B) ceramide. Item 2. The topical composition according to Item 1, wherein the (B) ceramide is human ceramide and / or pseudo-ceramide. Item 3. The topical composition according to Item 1 or 2, wherein the (B) ceramide is ceramide 2. Item 4. The topical composition according to any one of Items 1 to 3, wherein the (A) steroid anti-inflammatory agent is prednisolone and / or its ester. Item 5. The topical composition according to any one of Items 1 to 4, which is an emulsified preparation.

Effects of the Invention

[0009] According to the present disclosure, in a topical composition containing a steroid anti-inflammatory agent, a formulation prescription is provided that can suppress separation due to storage and has excellent storage stability.

Modes for Carrying Out the Invention

[0010] The topical composition of the present disclosure is characterized by containing (A) a steroid anti-inflammatory agent and (B) ceramide. Hereinafter, the topical composition of the present disclosure will be described in detail. In the present disclosure, the description of the numerical range "X to Y" refers to the range of X or more and Y or less.

[0011] [(A) Steroid anti-inflammatory agent] The topical composition of the present disclosure contains a steroid anti-inflammatory agent. A steroid anti-inflammatory agent is a known drug having a steroid nucleus or a structure derived therefrom.

[0012] The type of the steroid anti-inflammatory agent used in the present disclosure is not particularly limited and may be appropriately set according to the medicinal effects to be imparted. For example, prednisolone and its esters such as prednisolone valerate acetate, prednisolone acetate, prednisolone succinate; dexamethasone and its esters such as dexamethasone acetate, dexamethasone valerate, dexamethasone propionate; hydrocortisone and its esters such as hydrocortisone acetate, hydrocortisone butyrate; clobetasone butyrate, fluocinolone acetonide, beclomethasone propionate, betamethasone valerate, betamethasone dipropionate, betamethasone butyrate propionate, mometasone furoate, halcinonide, diflorasone acetate, clopetazol propionate, etc. Among these steroid anti-inflammatory agents, prednisolone and its esters are preferably used, and prednisolone valerate acetate is more preferably used. These steroid anti-inflammatory agents may be used alone or in combination of two or more.

[0013] Regarding the content of the steroid anti-inflammatory agent in the topical composition of the present disclosure, it may be appropriately set according to the medicinal effects to be imparted, the dosage form, etc. For example, it may be 0.001 to 1% by weight, preferably 0.001 to 0.5% by weight, more preferably 0.01 to 0.3% by weight, still more preferably 0.05 to 0.3% by weight, and particularly preferably 0.1 to 0.2% by weight.

[0014] [(B) Ceramide] The topical composition of the present disclosure contains ceramide in addition to the steroid anti-inflammatory agent. In the topical composition of the present disclosure, by containing ceramide, it becomes possible to suppress separation even though it contains a steroid anti-inflammatory agent.

[0015] In the present disclosure, ceramide includes human-type ceramide, pseudo-ceramide, animal-derived ceramide, and plant-derived ceramide. Human-type ceramide is a ceramide having the same structure as the ceramide present in human skin. Pseudo-ceramide is a ceramide chemically synthesized to resemble human-type ceramide. Animal-derived ceramide is a ceramide derived from mammals. Plant-derived ceramide is a ceramide derived from plants.

[0016] The ceramide used in the present disclosure may be any type of ceramide, but from the viewpoint of more effectively suppressing the separation of the topical composition, preferably human-type ceramide and pseudo-ceramide, and more preferably human-type ceramide.

[0017] Specific examples of human-type ceramide include ceramide 1, ceramide 2, ceramide 3, ceramide 4, ceramide 5, ceramide 6I, ceramide 6II, ceramide 7, ceramide 8, ceramide 9, ceramide 10, etc. Among these human-type ceramides, from the viewpoint of more effectively suppressing the separation of the topical composition, preferably ceramide 2 (N-stearoyl dihydrosphingosine) is mentioned.

[0018] Specific examples of the putative ceramide include N-(3-hexadecyloxy-2-hydroxypropyl)-N-2-hydroxyethyl hexadecanamide, trihydroxy palmitamide hydroxypropyl myristyl ether, cetyl hydroxyproline palmitamide, and the like.

[0019] In the present disclosure, the ceramide may be used alone or in combination of two or more.

[0020] In the topical composition of the present disclosure, the ratio of the steroid anti-inflammatory agent to the ceramide is, for example, 0.01 to 100 parts by weight, preferably 0.05 to 50 parts by weight, more preferably 0.1 to 30 parts by weight, still more preferably 1 to 25 parts by weight, and particularly preferably 3 to 20 parts by weight of the ceramide per 1 part by weight of the steroid anti-inflammatory agent.

[0021] Also, the content of the ceramide in the topical composition of the present disclosure is 0.001 to 10% by weight, preferably 0.001 to 8% by weight, more preferably 0.01 to 5% by weight, still more preferably 0.05 to 3% by weight, even more preferably 0.3 to 2.5% by weight, and particularly preferably 0.5 to 2.5% by weight.

[0022] [Water] The topical composition of the present disclosure contains water in order to be prepared into a desired dosage form. The content of water in the topical composition of the present disclosure may be appropriately set according to the dosage form and the like. For example, it is 20 to 97% by weight, preferably 25 to 95% by weight, more preferably 30 to 90% by weight, still more preferably 35 to 80% by weight.

[0023] [Polyhydric alcohol] The external composition of the present disclosure may contain a polyhydric alcohol as necessary. The type of polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable. Examples include dihydric alcohols such as ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, and polypropylene glycol; and trihydric alcohols such as glycerin. Among these polyhydric alcohols, 1,3-butylene glycol is preferably mentioned. These polyhydric alcohols may be used alone or in combination of two or more.

[0024] When the external composition of the present disclosure contains a polyhydric alcohol, its content is not particularly limited. For example, it may be 1 to 15% by weight, preferably 1 to 10% by weight, more preferably 2 to 8% by weight.

[0025] [Surfactant] The external composition of the present disclosure may contain a surfactant to prepare a desired dosage form. The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, or an amphoteric surfactant, but preferably a nonionic surfactant.

[0026] The type of nonionic surfactant is not particularly limited as long as it is pharmaceutically acceptable. Examples include polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters, lecithin derivatives, and the like. Among these, examples of suitable nonionic surfactants include polyoxyethylene sorbitan fatty acid esters and polyoxyethylene hydrogenated castor oil. These nonionic surfactants may be used alone or in combination of two or more.

[0027] When a surfactant is contained in the external composition of the present disclosure, its content may be appropriately set according to the dosage form, the type of surfactant used, etc. For example, 0.1 to 20% by weight, preferably 0.5 to 10% by weight, more preferably 1 to 5% by weight can be mentioned.

[0028] [Thickener] The external composition of the present disclosure may contain a thickener as necessary for imparting viscosity, etc. The type of thickener is not particularly limited as long as it is pharmaceutically acceptable. For example, carboxyvinyl polymer, xanthan gum, guar gum, locust bean gum, carrageenan, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium alginate, propylene glycol alginate, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, acrylic acid methacrylic acid alkyl copolymer, sodium polyacrylate bentonite, dextrin fatty acid ester, pectin, etc. can be mentioned. Among these thickeners, carboxyvinyl polymer is preferably mentioned. These thickeners may be used alone or in combination of two or more.

[0029] When the external composition of the present disclosure contains a thickener, its content is not particularly limited. For example, 0.05 to 5% by weight, preferably 0.1 to 3% by weight, more preferably 0.1 to 1% by weight can be mentioned.

[0030] [Oil component] The topical composition of the present disclosure may contain an oil component in order to be prepared into a desired dosage form. The type of the oil component is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include mineral oil, fatty acid alkyl esters, vegetable oils, animal oils, cholesterol, higher fatty acids having 12 to 34 carbon atoms, higher monohydric alcohols having 12 to 34 carbon atoms, silicone oil, and the like.

[0031] Among these oil components, as an example, mineral oil and fatty acid alkyl esters can be mentioned. Specific examples of the mineral oil include paraffin, hydrogenated polyisobutene, liquid paraffin, gelled hydrocarbons (such as plastibase), ceresin, microcrystalline wax, petrolatum, and the like. Examples of the fatty acid alkyl esters include esters of fatty acids having 6 to 30 carbon atoms and alcohols having 1 to 34 carbon atoms. Specific examples thereof include diisopropyl adipate, isopropyl myristate, isopropyl palmitate, cetyl palmitate, diethyl sebacate, ethyl oleate, and the like.

[0032] These oil components may be used alone or in combination of two or more.

[0033] When the topical composition of the present disclosure contains an oil component, the content thereof may be appropriately set according to the dosage form and the like. Examples thereof include 1 to 80% by weight, preferably 5 to 70% by weight, more preferably 5 to 50% by weight, and still more preferably 10 to 40% by weight.

[0034] [Other Components] In addition to the aforementioned components, the topical composition of the present disclosure may contain other commonly used additives as necessary. Examples of such additives include monohydric lower alcohols, pH adjusters, buffers, solubilizers, antiseptics, preservatives, antioxidants, stabilizers, fragrances, colorants, and the like. When these additives are contained in the topical composition of the present disclosure, the content thereof may be appropriately set according to the type of the additive to be used and the like.

[0035] In addition to the aforementioned components, the topical composition of the present disclosure may also contain a pharmacological component. Examples of such pharmacological components include antihistamines, local anesthetics, humectants, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used alone or in combination of two or more. Further, in the topical composition of the present disclosure, when these pharmacological components are contained, the concentration thereof may be appropriately set according to the type of pharmacological component used, the expected effect, and the like.

[0036] [Formulation type] The topical composition of the present disclosure may be an emulsion formulation such as an oil-in-water emulsion formulation or a water-in-oil emulsion formulation, or may be a non-emulsion formulation such as a solubilized formulation or an aqueous ointment. Originally, when a steroid anti-inflammatory agent is contained in an emulsion formulation (especially an oil-in-water emulsion formulation), separation due to storage tends to be remarkable. However, in the topical composition of the present disclosure, even if it is an emulsion formulation, separation due to storage can be effectively suppressed. In view of such an effect, preferred examples of the topical composition of the present disclosure include emulsion formulations, and more preferably oil-in-water emulsion formulations.

[0037] The dosage form of the topical composition of the present disclosure is not particularly limited as long as it can be applied transdermally, and it may be in any form such as liquid, semi-solid (cream-like, gel-like, ointment-like, paste-like), solid, etc., but preferably liquid or semi-solid.

[0038] In addition, the topical composition of the present disclosure is used as a topical skin pharmaceutical (including quasi-drugs). Specific examples of the formulation form of the topical composition of the present invention include creams, lotions, gels, emulsions, solutions, poultices, patches, liniments, aerosols, aqueous ointments, packs, and the like. Among these, creams and emulsions are preferably mentioned.

[0039] [Manufacturing method] The external composition of the present disclosure can be manufactured according to known formulation methods according to its dosage form. For example, when the external composition of the present disclosure is an emulsion formulation, the components to be contained are divided into water-soluble components and oil components, an aqueous phase containing the water-soluble components and an oil phase containing the oil components are prepared, and these are emulsified according to known methods to prepare.

Examples

[0040] Examples are shown below to more specifically explain the present disclosure, but the present disclosure is not limited thereto.

[0041] Test Example An external composition (an oil-in-water type emulsion formulation in emulsion form) having the composition shown in Table 1 was prepared. Specifically, prednisolone valerate acetate, ceramide 2, pseudo-ceramide, isopropyl myristate, white petrolatum, liquid paraffin, polyoxyethylene hydrogenated castor oil 50, and polysorbate 60 were mixed in predetermined amounts and heated and dissolved at 80°C to prepare an oil-phase composition. Separately, an aqueous-phase composition was prepared by mixing 1,3-butylene glycol, carboxyvinyl polymer, and purified water in predetermined amounts. Next, the aqueous-phase composition heated to 80°C was gradually added to the oil-phase composition heated to 80°C, mixed, and an emulsification operation was performed to obtain an external composition (an oil-in-water type emulsion formulation in emulsion form). The external compositions immediately after production were all in an emulsified state without separation.

[0042] 6 g of each external composition immediately after preparation was filled into a 10-ml glass bottle and stored for 5 days under light-shielded conditions at 60°C. The appearance of each external composition after storage was visually observed, and the stability was evaluated according to the following criteria. <Stability Criteria> AA: Not separated (Separation cannot be visually recognized in either the upright or tilted state of the glass bottle, and it maintains the same state as immediately after preparation). A: Slightly separated (Separation cannot be visually recognized when the glass bottle is upright, but slight separation can be visually recognized when the glass bottle is tilted). B: Slightly separated (Separation can be visually confirmed in either the upright or tilted state of the glass bottle, but the degree of separation is slight and within the allowable range). C: Separated (Obvious separation is observed, and the separated state can be clearly visually confirmed without tilting the glass bottle). D: Significantly separated (Obvious and distinguishable separation is observed at a glance).

[0043] The results are shown in Table 1. In the topical composition not containing prednisolone valerate acetate and ceramide, no separation occurred after storage, and it had excellent storage stability (Reference Example 1). However, in the topical composition containing prednisolone valerate acetate, significant separation was observed after storage (Comparative Example 1). In contrast, in the topical composition containing prednisolone valerate acetate and ceramide, separation after storage was suppressed (Examples 1 to 10). In particular, when ceramide 2 was used as the ceramide, separation after storage could be significantly suppressed (Examples 1 to 5).

[0044]

Table 1

[0045] Manufacturing Example The topical compositions (oil-in-water emulsion preparations in emulsion form) shown in Tables 2 to 4 were prepared in the same manner as in the above test examples. For each of the obtained topical compositions, the stability after storage at 60°C for 5 days was evaluated in the same manner as in the above test examples. As a result, for all of them, separation after storage could be significantly suppressed.

[0046]

Table 2

[0047]

Table 3

[0048]

Table 4

Claims

Claim 1 An external composition containing (A) a steroid anti-inflammatory agent and (B) ceramide. Claim 2 The external composition according to claim 1, wherein the (B) ceramide is human ceramide and / or pseudo-ceramide. Claim 3 The external composition according to claim 1 or 2, wherein the (B) ceramide is ceramide 2. Claim 4 The external composition according to claim 1 or 2, wherein the (A) steroid anti-inflammatory agent is prednisolone and / or its ester. Claim 5 The external composition according to claim 1 or 2, which is an emulsified preparation.

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