KR20080114558A - Steroid-containing o/w type emulsions - Google Patents

Abstract

An O/W type emulsion containing steroid and petrolatum is provided to ensure excellent appearance stability and moisturizing effect and to prevent the separation at a high temperature. An O/W type emulsion formulation comprises steroid, petrolatum, methyl cellulose, non-ionic surfactant and water. The steroid is a valeric acid prednisolone acetate. The separation inhibitor of O/W type emulsion formulation comprises steroid and petrolatum containing methyl cellulose as an active ingredient.

Description

O / K type emulsifying formulation containing steroids {STEROID-CONTAINING O / W TYPE EMULSIONS}

The present invention relates to 0 / W type emulsifying formulations containing steroids, and separation inhibitors thereof.

Background Art Conventionally, medicines containing steroids as active ingredients have been widely used as therapeutic agents for various inflammatory diseases. For example, an external preparation for skin containing an corticosteroid having an anti-inflammatory action as an active ingredient is used as a therapeutic agent for inflammatory skin diseases. As external preparations containing such steroids, creams, milky lotions and lotions are known in addition to oil-based ointments. In particular, 0 / W type emulsifying formulations containing steroids formulated with petroleum jelly as moisturizers and bases are less commercially available than W / O type emulsifying formulations and have a high usability. It is becoming.

However, the 0 / W type emulsion formulation containing steroid and petrolatum has a problem that the emulsion system tends to become unstable, and is separated over time, and the appearance stability is poor, especially under a high temperature environment.

In order to solve the problem which isolate | separates with such progress, various formulation examination is performed until now. For example, a skin external pharmaceutical formulation comprising valeric acid prednisolone, diphenhydramine, an organic modified clay mineral, a nonionic surfactant having an HLB of 3 to 13, and an oil (see Patent Document 1). ), Oil containing 2-40 mass% of valeric acid prednisolone and polar oil in the total mass of the preparation, and 10-50 mass% in the total oil, and one or two or more nonionic and / or ionic The polyhydric alcohol heavy oil type external skin medical emulsifying agent (refer patent document 2) etc. which contain surfactant and the polyhydric alcohol which has a 2 or more hydroxyl group in a molecule | numerator are known.

However, these prior arts describe nothing about the inhibitory effect of separation of the 0 / W type emulsion containing steroid and petrolatum by methylcellulose.

[Patent Document 1] Japanese Unexamined Patent Publication No. 2005-200328

[Patent Document 2] Japanese Unexamined Patent Publication No. 2005-320257

An object of the present invention is to suppress separation of a 0 / W type emulsion formulation containing steroid and petrolatum, and to obtain a formulation having high stability.

The present inventors have made diligent studies in view of these circumstances, and as a result, methylcellulose inhibits the separation over time of the 0 / W type emulsion containing steroids and petrolatum, in particular under high temperature environment, and when used, the appearance stability This favorable formulation was found and the present invention was completed.

That is, the present invention provides a 0 / W type emulsion formulation containing steroids, petrolatum and methylcellulose.

Moreover, this invention provides the suppression agent of the 0 / W type | mold emulsifying formulation containing the steroid and petrolatum which have methylcellulose as an active ingredient.

According to the present invention, it is possible to provide a 0 / W type emulsion formulation containing steroids and petroleum jelly having excellent moisturizing property and feeling of use, and having good appearance stability, which does not separate well over time, especially under a high temperature environment. have.

By using the separation inhibitor of the present invention, it is possible to prevent the separation over time of the 0 / W type emulsion formulation containing steroid and petrolatum, in particular under high temperature environment, and to obtain a formulation having good appearance stability.

Although the steroid used for this invention is not specifically limited, In this invention, an corticosteroid is preferable, Specifically, for example, acetic acid hydrocortisone, acetic acid propionic acid hydrocortisone, prednisolone, methyl prednisolone , Methyl prednisolone acetate, valeric acid prednisolone, difluprenate, valeric acid diflucortolone, fluoxynolone acetide, fluoxycortide, fluoxynonide, harcinonoid, amsinonide Pivalate flumetazone, triamcinolone acetide, dexamethasone, dexamethasone acetate, dexamethasone valeric acid dexamethazone, dipropionate beta metazone, propionic acid beclomethasone, butyric acid clobetazone, propionic acid chlorate Betasol, acetic acid diflorazone, butyric acid propionic acid beta metazone And valeric acid prednisolone is particularly preferable.

As for content of a steroid, 0.01-1 mass%, especially 0.05-0.5 mass% are preferable in the 0 / W type | mold emulsifying formulation of this invention from a viewpoint of effectiveness, safety, and stability.

The petrolatum used for this invention is a component mainly mix | blended as a moisturizer, a base, etc., and white petrolatum is preferable.

The content of petrolatum is preferably from 0.1 to 30% by mass, more preferably from 5 to 20% by mass, particularly preferably from 10 to 20% by mass, in view of the moisturizing effect, usability and appearance stability. desirable. Moreover, when a formulation is high in viscosity, such as cream, 10-20 mass% is preferable, and when it is a formulation with low viscosity, such as an emulsion and a lotion agent, 5-15 mass% is preferable.

The methyl cellulose used for this invention is not specifically limited, Any methyl cellulose from which substitution rate, molecular weight, and a viscosity of a methoxy group differ may be used, and these can be used individually or in mixture of 2 or more types. From the viewpoint of solubility in water, the substitution rate of the methoxy group of the methyl cellulose is preferably 26 to 33%, and more preferably 27.5 to 31.5%. In addition, the quantification of the substitution rate of the methoxy group of the said methyl cellulose is performed in accordance with the quantification method of the methoxy group of the methyl cellulose described in the 15th revised Japanese pharmacy room. In addition, the viscosity of methyl cellulose is preferably in the range of 3 to 12000 mPa · s, more preferably in the range of 5 to 8000 mPa · s, more preferably in the range of 6 to 3000 mPa · s, in terms of separation inhibitory effect. The range of 300 mPa * s is still more preferable, and the range of 8-80 mPa * s is especially preferable. In addition, the viscosity measurement of the said methyl cellulose is performed according to the viscosity measuring method of methylcellulose described in the 15th revised Japanese pharmacy room. As such a methylcellulose, as a commercial item, for example, Metros SM-15 (substitution rate of methoxy group: 27.5-31.5%, viscosity: 15 mPa · s), Metros SM-100 (substitution rate of methoxy group: 27.5-31.5% , Viscosity: 100 mPa · s), Metros SM-400 (substitution rate of methoxy group: 27.5-31.5%, viscosity: 400 mPa · s), metros SM-4000 (substitution rate of methoxy group: 27.5-31.5%, viscosity: 4000 mPa S) (above, manufactured by Shin-Etsu Chemical Co., Ltd.) and the like, Metros SM-15 and Metros SM-400 are preferable, and Metros SM-15 is particularly preferable.

As for content of methyl cellulose, 0.01-3 mass% and 0.03-1 mass% are more preferable in the 0 / W type | mold emulsifying formulation of this invention from a separation inhibitory effect, usability, and manufacture viewpoint, and especially 0.05-0.5 mass% is desirable.

As for the content ratio (mass ratio) of the steroid and petrolatum in the 0 / W type | mold emulsion of this invention, 1: 3000-10: 1 are preferable respectively, 1: 400-1: 20 are more preferable, Especially 1: 400 -1:10 is preferable.

As for the content ratio (mass ratio) of petrolatum and methyl cellulose in the 0 / W type | mold emulsion of this invention, 1: 30-3000: 1 are preferable respectively, 20: 1-400: 1 are more preferable, Especially 10: 1-400: 1 are preferable.

As components other than the 0 / W type | mold emulsifying agent of this invention, oil, surfactant, and water other than petrolatum are mentioned.

The oils other than petrolatum used in the 0 / W type emulsion formulation of the present invention are not particularly limited as long as they are oil-soluble substances commonly used in the fields of medicines, cosmetics, etc., for example, hydrocarbons, fats and oils, and beeswax. And fatty acids, higher alcohols, ester oils, and the like, and particularly preferred are hydrocarbons and higher alcohols. Specific examples thereof include liquid paraffin, squalane and the like as cetolol and stearyl alcohol as higher alcohols.

Although content in particular other than petroleum jelly is not restrict | limited, Usually, 0.1-30 mass%, especially 1-20 mass% are preferable in the 0 / W type emulsion formulation of this invention.

As surfactant used for the 0 / W type | mold emulsion of this invention, a cationic surfactant, anionic surfactant, an amphoteric surfactant, and a nonionic surfactant are mentioned, Especially a nonionic surfactant is preferable.

Specific examples of the nonionic surfactants include propylene glycol mono fatty acid esters, ethylene glycol mono fatty acid esters, glycerin mono fatty acid esters, polyglycerine fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, methylglucoside fatty acid esters, alkylpolyglucosides, and the like. Polyhydric alcohol fatty acid esters or polyhydric alcohol alkyl ethers; Polyoxyethylene such as polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene phytosterol, polyoxyethylene phytostanol, polyoxyethylene cholesterol, polyoxyethylene cholestanol, polyoxyethylene polyoxypropylene alkyl ether Ether; Polyoxyethylene mono fatty acid ester, polyethylene glycol di fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene methyl glucoside fatty acid ester, polyoxyethylene castor oil Ether esters such as hardened castor oil, polyoxyethylene vegetable oil, polyoxyethylene alkyl ether fatty acid ester, polyoxyethylene polyoxypropylene glycol, and the like, and sorbitan fatty acid ester, polyoxyethylene hardened castor oil, and polyoxyethylene sorbent. Non-fatty fatty acid esters are preferred.

It is preferable that carbon number of the fatty acid in a sorbitan fatty acid ester and a polyoxyethylene sorbitan fatty acid ester is 12-20, It is more preferable that it is 16-20, It is especially preferable that it is 18. It is preferable that it is 5-100, and, as for the addition number of ethylene oxide in polyoxyethylene hardened castor oil, it is more preferable that it is 30-60.

Moreover, it is preferable that HLB of a nonionic surfactant is 2-18, and it is more preferable that it is 3-17. For example, it is preferable that HLB of sorbitan fatty acid ester is 2-9, and it is more preferable that it is 3-6. It is preferable that HLB of polyoxyethylene hardened castor oil is 10-17, and it is more preferable that it is 12-15. It is preferable that HLB of polyoxyethylene sorbitan fatty acid ester is 9-18, and it is more preferable that it is 14-17.

Although content in particular is not restrict | limited as surfactant, Usually, 0.1-10 mass% is preferable in the 0 / W type emulsion formulation of this invention, and 1-5 mass% is especially preferable.

Although content of the water in O / W type | mold emulsifying formulation of this invention changes with a dosage form, generally 35-95 mass%, especially 60-90 mass% is preferable. Moreover, as for content of water in the case of cream, 35-80 mass%, especially 60-75 mass% is more preferable. As for content of water in the case of an emulsion, 45-90 mass%, especially 70-85 mass% are preferable. As for content of water in the case of a lotion agent, 50-95 mass%, especially 75-90 mass% is preferable.

The 0 / W type emulsion formulation of this invention can be mix | blended in addition to the said component, and further combining various components individually or as needed as needed.

Such components are not particularly limited as long as they are generally used in external preparations in the fields of medicines, quasi-drugs, or cosmetics, and for example, bases, thickeners, preservatives, pH regulators, stabilizers, irritant agents, preservatives, colorants, In addition to dispersants and fragrances, pharmacologically active ingredients include local anesthetics, anti-inflammatory agents, anti-inflammatory agents, vitamins, antibacterial agents, antiviral agents, antifungal agents, wound healing agents, keratinizers, analgesics, moisturizers, whitening agents, astringents, antioxidants, and hair growth agents. Inhibitors, anti-wrinkle agents and the like.

Although the pH of the O / W type emulsion formulation of this invention is not specifically limited, At the time of 10-fold dilution with water, it is preferable that it is 3-7, especially 4-5 in 25 degreeC.

As the pH adjuster, for example, hydroxycarboxylic acids such as citric acid and salts thereof, alkyl hydroxide metal salts such as sodium hydroxide, alkyl hydroxide earth metal salts and the like can be used alone or in combination of two or more thereof.

It is preferable that it is 0.1-50 g, and, as for the roughness of the O / W type | mold emulsifying agent of this invention, it is more preferable that it is 0.5-30 g. The measurement of illuminance is performed here on the conditions of a 1 cm sphere, 1 cm entrance, and 30 cm / min (25 degreeC) by a rheometer (NRM-3002D-L: Floating Industry Co., Ltd. product).

Examples of the formulation of the 0 / W type emulsion formulation in the present invention include creams, emulsions, and lotions.

The 0 / W type emulsified formulation of the present invention contains steroid, petrolatum and methyl cellulose as essential components, and if necessary, other components can be appropriately blended within the range to exhibit the effects of the present invention and can be produced by a known method. For example, the aqueous phase in which methyl cellulose is dissolved, and the oil phase containing petroleum jelly are mixed after heating, emulsified under heating conditions such as 60 to 90 ° C, cooled, and then prepared by adding a steroid.

Although the separation inhibitor of this invention makes the said methyl cellulose an active component, although methyl cellulose can be used independently as it is, it may contain the other component generally used.

The separation inhibitor of the present invention can stabilize the emulsified state of the 0 / W type emulsion formulation containing steroid and petrolatum, can suppress separation over time, and maintain the appearance stability of the formulation. In particular, under a high temperature environment, the separation with time elapsed at 50 ° C to 80 ° C can be suppressed.

It is preferable to mix | blend the compounding quantity with respect to the formulation of a separation inhibitor so that it may become 0.01-3 mass%, especially 0.05-0.5 mass% with respect to the formulation mass as a mass of methyl cellulose.

Example

Example 1

Vaseline 15.0 g, liquid paraffin 5.0 g, cetanol 2.5 g, polyoxyethylene hardened castor oil (50E.O.) (Nichol HCO-50: Nippon Sapakant Industries Co., Ltd.) 1.0 g, monostearic acid polyoxy Eterene sorbitan (20E.O.) (Nicole TS-10: manufactured by Nippon Sapakantt Co., Ltd.) 1.5g, sorbitan monostearate (Nicole SS-10M: manufactured by Nippon Sapatant Co., Ltd.) 0.5 g and 0.1 g of parabens were dissolved by heating at 75 ° C (oil phase).

PH adjuster (citric acid and sodium hydroxide) so that the pH of the final formulation is set to 0.1 g of methyl cellulose (methose SM-400: manufactured by Shin-Etsu Chemical Co., Ltd.), 0.01 g of sodium edate, and 4.5 g of purified water (a final amount of the final formulation). ) Was dissolved and heated to 75 ° C. (water phase).

The oil phase and the water phase were mixed and emulsified at 75 ° C. After emulsification, the mixture was cooled to 50 ° C, 0.15 g of valeric acid prednisolone (manufactured by Joe Koo Pharmaceutical Co., Ltd.) was dispersed and mixed, and cooled to room temperature to obtain a cream.

Comparative Example 1

A cream was obtained in the same manner as in Example 1 except that the methyl cellulose of Example 1 was not mixed.

Comparative Examples 2 to 6

0.1 g of hydroxyethyl cellulose instead of the methyl cellulose of Example 1 (Comparative Example 2: CF-V, manufactured by Sumitomo Purification Co., Ltd.), 0.1 g of sodium alginate (Comparative Example 3: I-1, manufactured by Kimika Co., Ltd.) , 0.3 g of povidone (Comparative Example 4: K-90, manufactured by BASF), 0.3 g of Carmellose (Comparative Example 5: 1350, manufactured by Daicel Chemical Industries, Ltd.), or 0.1 g of sodium hyaluronate (Comparative Example 6 : It prepared similarly to Example 1 except having used HA12 and the Shiseido Co., Ltd. product, and the cream was obtained.

In addition, the compounding quantity of water-soluble polymer was adjusted and mix | blended so that it might be the same roughness as the cream which mix | blended methylcellulose.

Table 1 shows the ingredient names and the compounding amounts of the creams of Example 1 and Comparative Examples 1 to 6.

Test Example 1

In order to examine the external appearance stability of the prepared O / W type emulsion formulation, Example 1 and Comparative Examples 1-6 were filled in the glass bottle (2K bottle), respectively, and the presence or absence of the separation was confirmed. The presence or absence of separation was visually evaluated. (Circle) and thing which isolate | separation generate | occur | produced were made into what was not confirmed by separation. Observation period was made into an evaluation point immediately after manufacture and after 3 days storage at 60 degreeC. In addition, the measurement of the roughness was measured on the conditions of 1 cm sphere, 1 cm entrance, 30 cm / min (25 degreeC) by the rheometer (NRM-3002D-L: Floating Industry Co., Ltd. product).

The results are shown in Table 1.

Preparations except methyl cellulose (Comparative Example 1), hydroxyethyl cellulose (Comparative Example 2) instead of methyl cellulose, sodium alginate (Comparative Example 3), povidone (Comparative Example 4), carmellose (Comparative Example 5), hyaluronic acid O / W type emulsion formulations containing steroid and petrolatum formulated with sodium (Comparative Example 6) showed no separation immediately after preparation, but separation was also observed in any formulation when stored at 60 ° C for 3 days.

However, when methylcellulose was blended into 0 / W type emulsion formulation containing steroid and petrolatum, it was confirmed that no separation occurred even when stored at 60 ° C for 3 days, and it was a stable formulation.

Example 2

Vaseline 7.5 g, liquid paraffin 2.5 g, cetanol 0.25 g, stearyl alcohol 0.25 g, polyoxyethylene hardened castor oil (50E.O.) (Nicole HCO-50: manufactured by Nippon Sapakantt Co., Ltd.) 0.5 g , Monostearic acid polyoxyethylene sorbitan (20E.O.) (Nicole TS-10: manufactured by Nippon Sapakantt Co., Ltd.) 0.5 g, sesquioleic acid sorbitan (Nicole SO-15: Nippon Sapatant Industry 1.0g and 0.1 g of parabens were melt | dissolved by heating at 75 degreeC (oil phase).

0.3 g of carboxyvinyl polymer (Syntarene L: Wako Pure Chemical Industries, Ltd.), 0.1 g of methyl cellulose (Methods SM-15: Shin-Etsu Chemical Co., Ltd.), 0.01 g of sodium edate in purified water (amount of the final formulation total amount of 100 g) And pH adjusters (citric acid and sodium hydroxide) were dissolved so that the pH of the final formulation was 4.5 and heated to 75 ° C. (water phase).

The oil phase and the water phase were mixed and emulsified at 75 ° C. After emulsification, the mixture was cooled to 50 ° C, 0.15 g of valeric acid prednisolone (manufactured by Joe Koo Pharmaceutical Co., Ltd.) was dispersed and mixed, and cooled to room temperature to obtain a lotion agent.

Example 3

A lotion agent was obtained in the same manner as in Example 2 except that 0.3 g of methyl cellulose (Medose SM-15: manufactured by Shin-Etsu Chemical Co., Ltd.) was obtained.

Comparative Example 7

A lotion agent was obtained in the same manner as in Example 2 except that the methyl cellulose of Example 2 was not mixed.

Comparative Examples 8-12

0.1 g of hydroxyethyl cellulose instead of the methyl cellulose of Example 2 (Comparative Example 8: CF-V, manufactured by Sumitomo Purification Co., Ltd.), 0.1 g of sodium alginate (Comparative Example 9: I-1, manufactured by Kimika Co., Ltd.) 0.1 g of povidone (Comparative Example 10: K-90, manufactured by BASF), 0.1 g of Carmeloose (Comparative Example 11: 1350, manufactured by Daicel Chemical Industries, Ltd.), or 0.1 g of sodium hyaluronate (Comparative Example 12 : It prepared similarly to Example 2 except having used HA12 and the Shiseido Co., Ltd. product, and the lotion agent was obtained.

In addition, the compounding quantity of water-soluble polymer was adjusted and mix | blended so that it might be the same roughness as the lotion agent which mix | blended methylcellulose.

The component name and compounding quantity of the lotion agent of Example 2, Example 3, and Comparative Examples 7-12 are shown in Table 2.

Test Example 2

In order to examine the external appearance stability of the prepared O / W type | mold emulsifying formulation, Example 2, 3 and Comparative Examples 7-12 were filled in the glass bottle (2K bottle), respectively, and the presence or absence of the separation was confirmed. The presence or absence of separation was visually evaluated. (Circle) and thing which isolate | separation generate | occur | produced were made into what was not confirmed by separation. Observation period was made into an evaluation point immediately after manufacture and after 3 weeks storage at 60 degreeC. In addition, the measurement of the roughness was measured on the conditions of 1 cm sphere, 1 cm entrance, 30 cm / min (25 degreeC) by the rheometer (NRM-3002D-L: Floating Industry Co., Ltd. product).

The results are shown in Table 2.

Preparations other than methyl cellulose (Comparative Example 7), hydroxyethyl cellulose (Comparative Example 8) instead of methyl cellulose, sodium alginate (Comparative Example 9), povidone (Comparative Example 10), carmellose (Comparative Example 11), hyaluronic acid The 0 / W type emulsion formulation containing steroid and petrolatum formulated with sodium (Comparative Example 12) showed no separation immediately after preparation, but separation was observed in any formulation when stored at 60 ° C for 3 weeks.

However, when methylcellulose was blended into 0 / W type emulsion formulation containing steroid and petroleum jelly, it was confirmed that separation did not occur even if stored at 60 ° C for 3 weeks, and it was a stable formulation.

Claims (6)

0 / W type emulsion formulation containing steroids, petrolatum and methylcellulose. The method of claim 1, 0 / W type emulsion formulation wherein the steroid is valeric acid prednisolone. The method according to claim 1 or 2, Furthermore, O / W type emulsion formulation containing a nonionic surfactant and water. Separation inhibitor of 0 / W type emulsion formulation containing steroid and petrolatum which contain methylcellulose as an active ingredient. The method of claim 4, wherein Isolation inhibitor wherein the steroid is valeric acid prednisolone. The method according to claim 4 or 5, Separation inhibitor wherein the 0 / W type emulsion formulation further contains a nonionic surfactant and water.