JP2009114081A - O/w emulsion type skin care composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an O/W emulsion type skin care composition that has percutaneous absorption of steroidal anti-inflammatory agent, excellent sense of use and moisture retaining property of preparation and reduction in skin irritation and contains a steroidal anti-inflammatory agent. <P>SOLUTION: The O/W emulsion type skin care composition comprises (A) a steroidal anti-inflammatory agent, (B) an oily component having an organicity of ≤300 and an inorganicity of ≤200 by an organic conceptual diagram, (C) an acrylic acid-alkyl methacrylate copolymer, (D) a ≥16C alcohol and (E) an oily component selected from a nonpolar oil and a triglyceride. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an O / W emulsion type external composition for skin containing a steroidal anti-inflammatory agent.

  In a cream preparation containing a steroidal anti-inflammatory agent, the crystals of the steroid are dispersed in the aqueous phase. Oil-based bases such as ointments often use petrolatum or the like, and polar steroidal anti-inflammatory agents do not dissolve. Therefore, in any of the preparations, the transdermal absorbability of the steroidal anti-inflammatory agent was low, and the effect was not sufficiently exhibited. In addition, oil base preparations are sticky and have a problem of poor usability.

  In contrast, a technique has been proposed in which a poorly soluble drug is dissolved in a highly polar oil to enhance its transdermal absorbability. However, steroidal anti-inflammatory agents are extremely insoluble in water and oil, and when a highly polar oil is used for the dissolution, the emulsification system generally becomes unstable, making it difficult to produce a practical cream.

  In addition, a preparation using a large amount of highly polar oil has problems of lacking moisture retention and increased irritation to the skin. Moisturizing and hypoallergenicity are one of the important factors for the function of skin treatment drugs, and the therapeutic effect by enhancing transdermal absorbability by dissolving steroidal anti-inflammatory drugs, excellent formulation It has been desired to develop a composition containing a steroidal anti-inflammatory agent that combines a feeling of use and moisture retention and a reduction in skin irritation.

JP 2002-20316 A JP 2003-306411 A JP 2006-8620 A JP 2003-201231 A

  The present invention has been made in view of the above circumstances, and includes a steroidal anti-inflammatory agent that has a transdermal absorbability of a steroidal anti-inflammatory agent, an excellent usability and moisturizing property of the preparation, and a reduction in skin irritation. It is an object of the present invention to provide an O / W emulsion-type external composition for skin.

  As a result of intensive studies to achieve the above object, the present inventors have dissolved (A) a steroidal anti-inflammatory agent with (B) a specific oil component, and (C) an acrylic acid / alkyl methacrylate copolymer. It was discovered that the above problems can be solved by emulsifying and further forming (D) an alcohol having 16 or more carbon atoms and (E) a nonpolar oil or a triglyceride, thereby obtaining the present invention. It has been reached.

Accordingly, the present invention provides the following inventions.
[1]. (A) Steroidal anti-inflammatory agent, (B) Oil component with organic value of 300 or less and inorganic value of 220 or less according to organic conceptual diagram, (C) acrylic acid / alkyl methacrylate copolymer, (D) carbon number An O / W emulsified skin external composition containing 16 or more alcohols and an oily component selected from (E) nonpolar oil and triglyceride.
[2]. The O / W emulsion type skin external composition as described in [1], wherein the component (D) with respect to the component (B) is 40 to 65% by mass, and the component (E) with respect to the component (B) is 40 to 80% by mass.
[3]. (B) O / W emulsion type skin external composition as described in [1] or [2] whose component is a combination of benzyl alcohol and polybasic acid ester.
[4]. (D) O / W emulsion type skin external composition in any one of [1]-[3] whose component is alcohol chosen from cetyl alcohol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol.
[5]. (E) O / W emulsion type skin external composition in any one of [1]-[4] whose component is an oil-based component chosen from squalane, liquid paraffin, light liquid paraffin, and triglyceride.
[6]. (A) O / W emulsion type skin external composition in any one of [1]-[5] whose component is prednisolone valerate acetate or clobetasone butyrate.

  According to the present invention, an O / W emulsified type containing a steroidal anti-inflammatory agent, which has a transdermal absorbability of a steroidal anti-inflammatory agent, an excellent usability and moisturizing property of the preparation, and a reduction in skin irritation. An external composition for skin can be provided.

  The O / W emulsion type skin external composition of the present invention comprises (A) a steroidal anti-inflammatory agent, (B) an oil component having an organic value of 300 or less and an inorganic value of 220 or less according to an organic conceptual diagram, and (C) an acrylic. It contains an oily component selected from an acid / alkyl methacrylate copolymer, (D) an alcohol having 16 or more carbon atoms, and (E) a nonpolar oil and triglyceride.

  The (A) steroidal anti-inflammatory agent is not particularly limited as long as it is a fat-soluble, water-insoluble substance having a steroid nucleus (cyclopentano-perhydrophenanthrene nucleus) and is solid at room temperature (25 ° C.). (A) As steroidal anti-inflammatory agents, prednisolone valerate acetate, clobetasone butyrate, clobetasol propionate, diflorazone acetate, dexamethasone propionate, diflucortron valerate, fluocinonide, hydrocortisone butyrate propionate, diflupredonate, dipropionic acid Betamethasone, Amsinonide, Halsinonide, Budesonide, Mometasone furanate, Betamethasone butyrate propionate, Betamethasone valerate, Dexamethasone valerate, Deprodon propionate, Beclomethasone propionate, Fluocinolone acetonide, Hydrocortisone butyrate, Dexamethasone Alclomethasone acid, triamcinolone acetonide, dexamethasone acetate, methylprednisolone acetate, hydride acetate Cortisone, methylprednisolone and the like, can be used singly or in combination of two or more as appropriate. Among these, prednisolone valerate acetate and clobetasone butyrate are preferable.

  (A) Although the compounding quantity of a component is the effective amount, 0.01-3 mass% is preferable in an O / W emulsion type skin external composition, More preferably, it is 0.01-2 mass%, More preferably, it is 0. 0.01 to 1% by mass.

  (B) By using an oily component having an organic value of 300 or less and an inorganic value of 220 or less according to an organic conceptual diagram, the therapeutic effect of enhancing transdermal absorbability is enhanced by dissolving a steroidal anti-inflammatory agent. be able to. The organic value of the oil component is preferably 80 to 300, more preferably 100 to 300, and the inorganic value is preferably 60 to 220, more preferably 80 to 210.

  As component (B), benzyl alcohol (organic value / inorganic value = 140/115), N-methyl-2-pyrrolidone (100/210), diisopropyl adipate (220/120), diisopropyl sebacate (300 / 120), polybasic acid esters such as diethyl sebacate (280/120), and the like can be used singly or in appropriate combination of two or more. Among these, it is preferable to use benzyl alcohol in combination with one or more polybasic acid esters. By using in such a combination, the solubility of the component (A) in the composition can be further increased, and precipitation can be further suppressed. In particular, a combination of benzyl alcohol and diisopropyl sebacate, or a combination of benzyl alcohol and diisopropyl adipate is preferable.

  (B) As for the compounding quantity of a component, 3-10 mass% is preferable in an O / W emulsion type skin external composition, More preferably, it is 4-9 mass%. In addition, when mix | blending in combination of 2 or more types of (B) component, a compounding quantity is the total amount. When combining benzyl alcohol and one or more of the polybasic acid esters, 1 to 4% by mass of benzyl alcohol and 2 to 6% by mass of polybasic acid ester are preferable, and 1.5 to 4% by mass of benzyl alcohol 2.5-6 mass% of polybasic acid ester is more preferable. In the case of a combination of benzyl alcohol and diisopropyl sebacate, 2 to 4% by mass of benzyl alcohol and 3 to 6% by mass of diisopropyl sebacate are preferable, and 3 to 4% by mass of benzyl alcohol and 3 to 6% by mass of diisopropyl sebacate are more preferable. preferable.

  (C) Acrylic acid / alkyl methacrylate copolymer is a copolymer of acrylic acid and alkyl methacrylate, usually acrylic acid and 4 to 50 carbon atoms, preferably 8 to 40 carbon atoms, more preferably. Is a copolymer with an alkyl methacrylate having 10 to 30 alkyl groups. (C) A component can be used individually by 1 type or in combination of 2 or more types as appropriate.

  (C) As the acrylic acid / alkyl methacrylate copolymer, “Carbopol 1382 (Noveon) (C10-30)”, “PEMULEN TR-1 (Noveon) (C8-30)”, “PEMULEN” TR-2 (Noveon) (carbon number 8 to 30) ", both manufactured by Nikko Chemicals and the like.

  (C) As for the compounding quantity of a component, 0.1-0.5 mass% is preferable in an O / W emulsion type skin external composition, More preferably, it is 0.2-0.4 mass%.

  (D) Examples of the alcohol having 16 or more carbon atoms include cetyl alcohol (16 carbon atoms), stearyl alcohol (18 carbon atoms), cetostearyl alcohol (16,18 carbon atoms), aralkyl alcohol (20 carbon atoms), behenyl alcohol ( C22) etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. The upper limit of the carbon number is not particularly limited, but is preferably 24. The O / W emulsion type composition composed of the components (A) to (C) may become a hard gel emulsion, but it is uniform and stretched by blending the component (D). Thus, a creamy preparation with a good feeling of use can be obtained.

  As the component (D), cetyl alcohol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol are preferable, and cetyl alcohol and behenyl alcohol or stearyl alcohol are combined in terms of ease of taking with fingers and good shape retention. It is preferable to do.

  (D) As for the compounding quantity of a component, 1-5 mass% is preferable in an O / W emulsion type skin external composition, More preferably, it is 1.5-4 mass%. In addition, when mix | blending in combination of 2 or more types of (C) component, a compounding quantity is the total amount. When cetyl alcohol and behenyl alcohol are combined, cetyl alcohol 1-2 mass% and behenyl alcohol 1-2.5 mass% are preferable.

  Moreover, 40-65 mass% is preferable with respect to (B) component, ie, (D) component when (B) component is 100 mass%, More preferably, it is 41-64 mass%, More preferably, it is 45-64. % By mass. By setting it as this range, coexistence with percutaneous absorbability of (A) component and the outstanding usability can be aimed at more.

  (E) As an oil component chosen from nonpolar oil and triglyceride, it can be used individually by 1 type or in combination of 2 or more types. Examples of the nonpolar oil include squalane, liquid paraffin, and light liquid paraffin. Examples of the triglyceride include triglycerides mainly composed of unsaturated fatty acids such as palmitoleic acid, oleic acid, linoleic acid, and linolenic acid. In addition, oils containing triglycerides such as grape seed oil and olive oil can be used. Among them, squalane, light liquid paraffin, and triglyceride mainly composed of oleic acid are preferable. When using 2 or more types in combination, a combination of squalane or liquid paraffin and a triglyceride containing an unsaturated fatty acid as a main component is preferable from the viewpoint of moisture retention and a feeling of use.

  (E) As for the compounding quantity of a component, 3-7 mass% is preferable in an O / W emulsion type skin external composition, More preferably, it is 3-6 mass%, More preferably, it is 3-5 mass%, 2 or more types Is the total amount. When two or more types are used in combination, it is preferable to combine a nonpolar oil and a triglyceride, and the triglyceride is preferably 20 to 175% by mass relative to the nonpolar oil, that is, when the nonpolar oil is 100% by mass. More preferably, it is 25-170 mass%, More preferably, it is 30-170 mass%.

  Moreover, 40-80 mass% is preferable with respect to (B) component, ie, (E) component when (B) component is 100 mass%, More preferably, it is 42-78 mass%. By setting it as this range, coexistence with percutaneous absorbability of (A) component and reduction of moisture retention and skin irritation can be aimed at more. When the ratio of the component (E) to the component (B) is less than 40% by mass, the moisturizing property is lowered and the skin irritation is often remarkable, and when it exceeds 80% by mass, the solubility of the component (A) and This range is particularly preferred because the transdermal absorbability tends to decrease.

  The water content in the O / W emulsified skin external composition is preferably 70 to 90% by mass, more preferably 75 to 85% by mass, and the aqueous phase containing polyhydric alcohol or the like is 78 to 90% by mass. preferable. By setting the ratio of the amount of water and the water phase as described above, the effect of improving the transdermal absorbability and feeling of use of the component (A) can be further obtained.

  In the O / W emulsified skin external composition of the present invention, in addition to the above components, optional components used in the skin external composition are used alone or in combination of two or more, as long as the effects of the present invention are not impaired. Can be used. Optional components include polyoxyethylene hydrogenated castor oil, nonionic surfactants such as glyceryl monostearate, polyhydric alcohols such as propylene glycol and glycerin, pH adjusters, chelating agents, buffering agents, solid oils such as cetyl palmitate Etc.

  The external composition for skin of the present invention is an O / W emulsion type. By using an O / W emulsification type, practical use feeling and good transdermal absorbability can be compatible. In the case of an oil-based base such as an ointment, the percutaneous absorption rate is higher for an O / W emulsified composition than for an oil-based base because the formulation tends to be a more stable environment for the substance than in the skin. Become.

  Although it does not specifically limit as a manufacturing method of the O / W emulsion type skin external composition of this invention, In consideration of emulsification efficiency, a phase inversion emulsification method is preferable normally. That is, the (A) component, the (B) component, the (D) component, the (E) component and other oil components are mixed and uniformly dissolved at 70 to 80 ° C. to obtain an oil phase. Separately, water and other aqueous components are uniformly dissolved at 70 to 80 ° C. to obtain an aqueous phase. There is a method in which the component (C) is added to the oil phase prepared earlier, and the aqueous phase is slowly added while stirring at high speed using a homomixer or a disper at a constant temperature of 70 to 80 ° C. to obtain an emulsion.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%, and the ratio represents mass ratio. Further, unless otherwise specified, the amount of each component in the table is an amount converted into a pure component.

[Examples 1 to 18, Comparative Examples 1 to 4]
O / W emulsion type skin external compositions having the compositions shown in Tables 1 to 5 were prepared by the following method. About the obtained external composition for skin, evaluation mentioned later was performed. The results are also shown in the table.
<O / W emulsion type preparation method for external skin composition>
The component (A), component (B), component (D), component (E) and other oil components were mixed and dissolved uniformly at 70 to 80 ° C. to obtain an oil phase. Separately, water and other aqueous components were uniformly dissolved at 70 to 80 ° C. to obtain an aqueous phase. (C) component was added to the oil phase prepared previously, the water phase was added slowly, stirring at 4000 rpm using a disper at 70-80 degreeC constant temperature, and it emulsified for 5 minutes after addition. Thereafter, the mixture was gradually cooled to room temperature while stirring at a low speed of 500 rpm using a three-one motor to obtain an emulsion.

<Solubility of component (A)>
A small amount of specimen was placed on a slide glass, covered with a cover glass, and observed with a polarizing microscope (magnification: 400 times). Evaluation was made according to the following criteria, and “◎” and “○” were judged good.
[Evaluation criteria]
(Double-circle): (A) component melt | dissolves completely and a crystal | crystallization is not observed.
○: A very small amount of undissolved crystals are observed.
Δ: Crystals of various sizes are observed and are not completely dissolved.
X: The crystal structure of the component (A) is clearly observed and is not dissolved.

<Cream-like properties>
The properties of the specimens were observed and evaluated according to the following criteria, and “◯” was judged good.
[Evaluation criteria]
○: Appropriate viscosity and spread, uniform cream.
Δ: Viscosity is appropriate, but it is difficult to remove with fingers and does not spread.
X: Phase separation is not possible to prepare a composition for external use on skin (* 1), or it becomes a hard gel and is not creamy (* 2)
In the case of phase separation or gelation, the following moisturizing property, skin irritation, and transdermal absorbability were not evaluated, and are indicated by “−” in the table.

<Moisturizing>
For 5 panelists, the initial horny water content of the inner part of the upper arm was measured using a keratin water content measuring instrument (IBS: SKICON200) under a constant temperature and humidity of 25 ° C. and 60% RH. It was applied to the inner side of the upper arm. After resting at 25 ° C., 60% RH, constant temperature and humidity for 30 minutes, the specimen on the coated part was wiped off with alcohol cotton, and the amount of keratin moisture was measured again. When the initial amount of keratinous water was 100, the amount of keratinous water after 30 minutes was calculated, and the average value of five people was evaluated according to the following criteria. “◎” and “○” were judged as good.
[Evaluation criteria]
A: The average value is 200 or more with respect to the initial 100. B: The average value is 160 or more and less than 200. Δ: The average value is 120 or more and less than 160. X: The average value is less than 120.

<Skin irritation>
The animals used were guinea pig Harley females (Japan SLC Co., Ltd.), 7 weeks old, and the number of animals used was 3 / group. The sample dose was 0.03 mL / 2 cm × 2 cm, and it was applied to the flank skin by application and administered once / day 3 times. The skin reaction was observed at 24 hours, 48 hours, and 72 hours after administration and 24 hours, 48 hours, and 72 hours after administration, and evaluated according to the following skin reaction criteria of the Draize method. Average score: Σ (erythema + edema) / number of animals (3) was calculated. From the obtained average score, evaluation was performed based on the following criteria. “◎” and “○” were judged as good.

［評価基準］
◎：平均点が０〜１．０未満
○：平均点が１．０〜２．５未満
△：平均点が２．５〜４．０未満
×：平均点が４．０以上

[Evaluation criteria]
A: Average score is less than 0 to less than 1.0 B: Average score is less than 1.0 to less than 2.5 Δ: Average score is less than 2.5 to less than 4.0 ×: Average score is 4.0 or more

<Transdermal absorption>
(1) Preparation of skin sample A skin sample of 4 cm x 3 cm was collected from the back skin of hairless mice.
(2) Measurement of skin permeation component amount The obtained skin sample was fixed to a vertical diffusion cell (Frantz cell), and the amount of percutaneous absorption was measured. That is, the skin sample is sandwiched and fixed between the donor and receptor of the vertical diffusion cell so that the epidermis side is up, and the receptor side is filled with physiological saline, and then 1 mL of the specimen is added on the donor side skin. It was applied to the entire surface of the skin sample. The receptor solution was sampled 8 hours after the addition, and the skin permeation amount of the active ingredient was measured by high performance liquid chromatography. The measurement conditions are as shown in the table.

The amount of permeation of the skin when the amount of the component (A) in the applied specimen was 100% was calculated and evaluated according to the following criteria, and ◎ and ○ were judged to be good.
[Evaluation criteria]
◎: 15% or more ○: 10% or more and less than 15% △: 5% or more and less than 10% ×: 5% or less

The raw materials used in Examples and Comparative Examples are shown below.

Claims (6)

  (A) Steroidal anti-inflammatory agent, (B) Oil component with organic value of 300 or less and inorganic value of 220 or less according to organic conceptual diagram, (C) acrylic acid / alkyl methacrylate copolymer, (D) carbon number An O / W emulsified skin external composition containing 16 or more alcohols and an oily component selected from (E) nonpolar oil and triglyceride.   The O / W emulsion type skin external composition of Claim 1 whose (D) component with respect to (B) component is 40-65 mass%, and (E) component with respect to (B) component is 40-80 mass%.   The O / W emulsion type skin external composition according to claim 1 or 2, wherein the component (B) is a combination of benzyl alcohol and a polybasic acid ester.   The O / W emulsified skin external composition according to any one of claims 1 to 3, wherein the component (D) is an alcohol selected from cetyl alcohol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol.   The component (E) is an oily component selected from squalane, liquid paraffin, light liquid paraffin, and triglyceride. The O / W emulsion type skin external composition according to any one of claims 1 to 4.   The component (A) is prednisolone valerate acetate or clobetasone butyrate but the O / W emulsified skin external composition according to any one of claims 1 to 5.