JP2011219369A - Emulsified skin care preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a creamy emulsified skin care preparation for external use stably blended with ufenamate, having excellent feeling of use (non-sticky feeling, perky feeling and fluffy sense) and also having excellent long term storage stability in a wide temperature region from low temperature to high temperature.SOLUTION: The emulsified skin care preparation for external use contains: (a) ufenamate; (b) glycerol fatty acid monoester; and (c) polyoxyethylene (2 to 50 mol-added) alkyl ether, wherein the (b) component/(c) component=0.1 to 1.3 (mass ratio).

Description

  The present invention relates to a pharmaceutical emulsion for external use on the skin. More specifically, a creamy external pharmaceutical emulsion containing a stable blend of ufenamate, excellent feeling in use (no stickiness, firmness and plumpness) and excellent long-term storage stability in a wide temperature range from low to high temperatures. Relates to the formulation.

  Ufenamate (= flufenamate butyl), which is a non-steroidal anti-inflammatory analgesic, is a poorly water-soluble drug, so it is generally dissolved in an oily base and blended into an external preparation for skin. As the dosage form of the external preparation for skin, emulsified external preparations such as creams and emulsions (= oil-in-water type (O / W type) or water-in-oil type (W / O type) emulsion preparation)) are mainly used.

  Conventionally, as a technique for stably blending a poorly water-soluble drug such as ufenamate into an oil-in-water emulsion preparation, a method of making the preparation into a fine emulsion has been known (for example, Patent Documents 1 and 2). Patent Document 3 discloses an emulsification in which silicone oil or an oil component having a dielectric constant of 4.0 or more is blended in order to suppress whitening after applying an emulsified preparation containing a medicinal component such as a polysulfate ester compound of chondroitin. In addition to chondroitin polysulfate compounds, Ufenamate is described as a medicinal component ([0019]).

  As described above, the stability of oil-in-water emulsion formulations has been solved by controlling the size of the emulsified particles. However, the effect of the combination of emulsifiers (surfactants) on the formulation stability As far as the present inventors know, the documents described and discussed are not known so far.

JP 2001-97859 A JP 2002-193790 A Japanese Patent Laid-Open No. 2002-205937

  The present invention has been made in view of the above-mentioned conventional circumstances, stably blending ufenamate, excellent in feeling of use (no stickiness, firmness and plumpness), and stored for a long time in a wide temperature range from low to high temperatures. An object of the present invention is to provide a creamy external pharmaceutical emulsion formulation having excellent stability.

  In order to solve the above-mentioned problems, the present invention comprises (a) ufenamate, (b) glycerin fatty acid monoester, (c) polyoxyethylene (2 to 50 mol addition) alkyl ether, and (b) component / ( c) A topical pharmaceutical emulsified preparation is provided that contains component = 0.1-1.3 (mass ratio).

  The present invention further provides the above-mentioned external skin pharmaceutical emulsion preparation, further comprising (d) a solid to semi-solid oil containing a higher aliphatic alcohol.

  The present invention further provides the above-mentioned pharmaceutical preparation for external application to skin, further comprising (e) a water-soluble polymer mainly composed of polyvinyl alcohol.

  Moreover, this invention provides the said skin external pharmaceutical emulsion formulation which further contains a carboxy vinyl polymer in (e) component.

  Moreover, this invention provides the said skin external pharmaceutical emulsion formulation which contains a polysaccharide water-soluble polymer further in (e) component.

  In addition, the present invention provides the above-mentioned external skin pharmaceutical emulsion preparation further containing vitamin A oil and / or tocopherol acetate.

  The present invention also provides the above-mentioned external skin pharmaceutical emulsion preparation, which is an oil-in-water emulsion external skin pharmaceutical emulsion preparation.

  According to the present invention, a creamy external pharmaceutical emulsion emulsified with a stable blend of ufenamate, excellent in feeling of use (no stickiness, firmness and plumpness) and excellent in long-term storage stability in a wide temperature range from low to high temperatures. A formulation is provided.

  Hereinafter, the present invention will be described in detail. In the following, POE represents polyoxyethylene, POP represents polyoxypropylene, and POB represents polyoxybutylene.

Ufenamate as a component (a) used in the present invention is known as a non-steroidal anti-inflammatory agent and is represented by the chemical formula C ₁₈ H ₁₈ F ₃ NO ₂ , and the chemical name is butyl O-[[3- (trifluoro Methyl) phenyl] amino] -benzoate. Ufenamate is effective against various skin diseases that cause inflammation and itchiness (for example, atopic dermatitis, seborrheic eczema, acute eczema, chronic eczema, diaper dermatitis, perioral dermatitis, shingles, etc.)・ It is known to work.

  The compounding amount of the component (a) is not particularly limited, and may be an amount sufficient for the expression of the drug effect, and may be appropriately increased or decreased depending on the purpose of treatment, patient age, body weight, disease progression, etc. In general, however, it is preferably blended in an amount of approximately 1 to 10% by mass, more preferably 1 to 6% by mass, based on the total amount of the pharmaceutical preparation for external use of the present invention. If it is less than 1% by mass, it is difficult to sufficiently exert the medicinal effect of the component (a). On the other hand, if it exceeds 10% by mass, the viewpoint of effective utilization of resources and the stability of the preparation are somewhat unstable, which is not preferable.

  In the present invention, the emulsifier contains (b) glycerin fatty acid monoester and (c) polyoxyethylene (2 to 50 mol addition) alkyl ether, and (b) component / (c) component = 0.1 to 1.3 (mass) Ratio). Thereby, in addition to the stable blending of component (a), usability effects and storage stability of the preparation can be obtained.

  (B) As a fatty acid which comprises a component, a C8-C24 saturated or unsaturated fatty acid is preferable. Further, it may be linear or branched. Specific examples of fatty acids include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, 2-palmitynic acid, petrothelic acid, oleic acid, elaidic acid, ricinoleic acid, linoleic acid, linolenic acid, Examples include arachidonic acid, isostearic acid, and 1,2-hydroxystearic acid. In the present invention, a fatty acid glycerin monoester having 12 to 20 carbon atoms is preferred, and glyceryl monostearate is particularly preferred. (B) A component can use 1 type (s) or 2 or more types.

  (C) What contains a C12-C22 alkyl group as an alkyl group in a component is preferable, and what contains a lauryl group, a cetyl group, an oleyl group, a stearyl group, a behenyl group etc. is preferable. Specific examples of the component (c) include POE behenyl ether, POE stearyl ether, POE cetyl ether and the like. Of these, POE (20) behenyl ether, POE (30) behenyl ether, and the like are particularly preferable. (C) A component can use 1 type (s) or 2 or more types.

  The amount of component (b) and component (c) is (b) component / (c) component = 0.1 to 1.3 (mass ratio), preferably 0.1 to 1.0 (mass ratio). ). When the blending ratio of the component (b) and the component (c) is out of the above range, the storage stability and the feeling of use (especially the feeling of stickiness) are poor. The total amount of component (b) and component (c) is preferably 0.5 to 3% by mass, more preferably 1 to 2% by mass. By making the total compounding quantity of (b) component and (c) component in the said range, especially storage stability can be improved much more effectively.

  In the present invention, (d) a solid to semi-solid oil containing a higher aliphatic alcohol can be blended. Examples of the higher aliphatic alcohol include higher aliphatic alcohols that are solid at room temperature, such as behenyl alcohol, stearyl alcohol, cetyl alcohol, and batyl alcohol. When the component (d) is blended, the higher aliphatic alcohol and the hydrophilic surfactant form an aggregate formed in water and sufficiently solidify to form a gel that prevents creaming. The gel is formed with [(b) component and (c) component] :( d) component = 1: 3 (molar ratio). Therefore, the higher aliphatic alcohol may be contained in an amount necessary for the gel formation, but is preferably contained in an excessive amount. The solid to semi-solid oil component other than the higher aliphatic alcohol contained in the component (d) is not particularly limited as long as it is a solid or semi-solid oil component at room temperature generally used for external preparations for skin. , Solid paraffin, microcrystalline wax, ceresin, barico wax, polyethylene wax, silicone wax, carnauba wax, beeswax (= beeswax), candelilla wax, jojoba wax, shellac wax, whale wax, molefish, lanolin, reduced lanolin, hard lanolin, etc. Waxes; higher fatty acids that are solid at room temperature such as myristic acid, palmitic acid, stearic acid, behenic acid; cocoa butter, hydrogenated castor oil, hydrogenated oil, hydrogenated palm oil, palm oil, hydrogenated palm oil, petrolatum, various Water-added animal and vegetable oils, fatty acid monocarboxylic acid lanolin al Ruesuteru, and the like. In the present invention, it is particularly preferable to use a solid or semi-solid hydrocarbon oil such as microcrystalline wax, polyethylene wax, and petroleum jelly from the viewpoint of usability.

  When the component (d) is blended, the total blending amount is preferably 1 to 20% by mass, more preferably 1.5 to 5% in the pharmaceutical preparation for external application to the skin of the present invention, from the viewpoints of elasticity, plump feeling and the like. 10% by mass.

  In the present invention, further, (e) a water-soluble polymer containing polyvinyl alcohol as a main component can be blended in order to improve elasticity. Specifically, the polyvinyl alcohol is preferably blended in the component (e) at a ratio of 50% by mass or more, more preferably 60% by mass or more. By containing polyvinyl alcohol as a main component, a firm feeling and a plump feeling can be effectively obtained.

  The component (e) can further contain a carboxyvinyl polymer. By blending the carboxyvinyl polymer, the firmness can be obtained more effectively.

  The component (e) can contain a polysaccharide water-soluble polymer in addition to polyvinyl alcohol. Examples of the polysaccharide water-soluble polymer include gum arabic, gum tragacanth, guar gum, carrageenan, xanthan gum, succinoglycan, casein, gelatin, succinoglucan and the like. In the present invention, xanthan gum is particularly preferably used from the viewpoint of improving the feeling of plumpness. When mix | blending xanthan gum, it is preferable to mix | blend in the ratio of about 5-20 mass% with respect to (e) component.

  (E) When mix | blending a component, it is preferable to mix | blend the total compounding quantity in the ratio of 0.4 mass% or more in this invention external pharmaceutical emulsion formulation, More preferably, it is 0.5 mass% or more. By blending the component (e) at a ratio of 0.4% by mass or more, sufficient firmness can be more effectively obtained. The upper limit of the amount is not particularly limited, but is preferably about 1.0% by mass or less from the viewpoint of feeling of use. If the amount is too large, a sticky feeling or twisting is likely to occur.

  In the present invention, a liquid oil can be blended as the oil in addition to the solid to semi-solid oil. The liquid oil component refers to a fluid oil component that does not volatilize at room temperature (25 ° C.). Specifically, for example, hydrocarbon oils such as liquid paraffin, squalane, olefin oligomer, light isoparaffin (= light liquid paraffin); 2-ethylhexanoic acid triglyceride, 2-ethylhexanoic acid cetyl, 2-ethylhexanoic acid pentaerythritol , Ester oils such as 2-ethylhexanoic acid trimethylolpropane, 2-ethylhexyl palmitate, isocetyl isononanoate, isopropyl myristate, cetyl 2-ethylhexanoate, diethyl sebacate, diethyl adipate; jojoba oil, olive oil, macadamia nut oil , Cottonseed oil, tea seed oil, safflower oil, rice bran oil, and other natural plant oils; decamethylpentacyclosiloxane, octamethyltetracyclosiloxane, dimethylpolysiloxane, methylphenylpolysiloxane Which silicone oil, and the like, can of course not be limited to these examples.

  In the present invention, not only the component (a) but also other oil-soluble drug components (for example, vitamin A oil, tocopherol acetate, etc.) are blended stably as the drug components. be able to.

  The skin external pharmaceutical emulsified preparation of the present invention can be either an oil-in-water type or a water-in-oil type, but is preferably an oil-in-water type.

  The pharmaceutical preparation for external use of the skin of the present invention can be prepared by a conventional method, and the emulsifying method is not particularly limited. For example, in the case of an oil-in-water emulsion formulation, the oil phase (inner phase) and the water phase (outer phase) are each heated to about 70 ° C., and the heated oil phase is gradually added to the water phase. The method of emulsifying with, and then cooling to room temperature is mentioned, but it is not limited to this.

  In the oil-in-water emulsified skin external preparation, the amount of the oil phase (inner phase) is usually about 10 to 30% by mass in the total amount of the skin external preparation. The reason is that if it exceeds 30% by mass, emulsification failure occurs, which is not preferable in terms of stability. However, in the present invention, particularly by blending the component (b) and the component (c) at the above blending ratio, the hardness does not decrease even when the blending amount of the oil phase (inner phase) exceeds 30% by mass. It has the effect of maintaining a creamy shape and excellent drug stability.

  In the oil-in-water type skin external pharmaceutical emulsion preparation of the present invention, in addition to the above-described blending components, other optional additive components that are usually used for skin external preparations within a range not impairing the effects of the present invention, for example, surfactants (Other than (b) component, (c) component), UV absorber, sequestering agent, lower alcohol, polyhydric alcohol, powder component, sugar, amino acid and salt thereof, organic amine, polymer emulsion, pH adjuster, Skin nutrients, vitamins, antioxidants, antioxidant assistants, fragrances and the like can be appropriately blended as necessary.

  Other ingredients that can be blended include, for example, preservatives (methyl paraben, ethyl paraben, butyl paraben, etc.); anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc.); whitening agents (For example, cypress extract, arbutin, etc.); various extracts (eg, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe, mallow, iris, grape, yokuinin, loofah, lily, saffron , Senkyu, Shokyu, Hypericum, Onis, Garlic, Pepper, Chimpi, Toki, Seaweed, etc.), Activator (eg, Royal Jelly, Photosensitizer, Cholesterol derivative, etc.); Blood circulation promoter (eg, Nonylate Wallenylamide, Nicotine) Benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, tocopherol nicotinate, inositol hexanicotinate, cyclandrate, cinnarizine, trazoline, acetylcholine, verapamil, cephalanthin , Γ-oryzanol, etc.); antiseborrheic agents (eg, sulfur, thianthol, etc.); anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.), antihistamine agents (eg, diphenhydromine hydrochloride), and the like. However, it is not limited to these examples.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited thereto. Unless otherwise specified, all the amounts are mass%.

  First, the test method and evaluation method used in this example will be described.

[Storage stability (after 1 day, 4 weeks)]
After each sample was prepared, the appearance (glossiness, presence / absence of elasticity) after one day (at 25 ° C.) was visually observed and evaluated based on the following evaluation criteria.

Further, after each sample was prepared, it was left in a thermostatic bath at −5 ° C., 0 ° C. and 50 ° C. for 4 weeks, and the appearance (glossiness, presence / absence of elasticity) was visually observed and evaluated based on the following evaluation criteria.
(Evaluation criteria)
○: The surface was glossy and was soft without elasticity ○ △: The surface was slightly glossy and slightly elastic, but there was no problem in practical use △: Surface No gloss, slightly elasticized property ×: No surface gloss, elasticized property

[A feeling of use (harness)]
Based on the following evaluation criteria, the sense of firmness when each sample was applied to the skin was evaluated by a female professional panel (10 persons).
(Evaluation criteria)
◎: 8 or more people answered that they are excellent in elasticity ○: 6-7 people answered that they were excellent in elasticity ○ △: 5-6 people answered that they were excellent in elasticity △: 3-4 people answered Answered that the feeling is excellent ×: 2 or less responded that the feeling was excellent

[Usage (puffiness)]
A feeling of plumpness when each sample was applied to the skin was evaluated based on the following evaluation criteria by a female professional panel (10 persons).
(Evaluation criteria)
◎: 8 or more respondents with excellent plump feeling ○: 6-7 respondents with excellent plump feeling ○ △: 5-6 respondents with excellent plump feeling △: 3-4 respondents Answered that the feeling of plump is excellent ×: 2 or less responded that the feeling of plump was excellent

[Usage feeling (no stickiness)]
A female professional panel (10 persons) evaluated the absence of stickiness when each sample was applied to the skin based on the following evaluation criteria.
(Evaluation criteria)
◎: 8 or more respondents said that they were not sticky. ○: 6-7 responded that they were not sticky. ○ △: 5-6 responded that they were not sticky. △: 3-4 respondents said that they were not sticky x: 2 or less responded that they were not sticky

[Comprehensive evaluation]
A (pass): All 6 evaluation items have no △, × evaluation, usability evaluation (3 items) are all ◎ evaluation, storage stability evaluation (3 items) are all ○ evaluation B (pass): all There were no △ and × evaluations among the 6 evaluation items, 1 or 2 evaluations in the usability evaluation (3 items), and 1 or less evaluations in ○ △, and ○ evaluations in the storage stability evaluation (3 items). 1 or 2 and ○ △ Evaluation is 1 or less C (failed): In all 6 evaluation items, there are 1 or more of △ and × Evaluation (Example 1: Storage stability, use Sex assessment)
Samples having the compositions shown in Table 1 below were prepared by conventional methods, and storage stability and usability were evaluated according to the above test methods and evaluation criteria. The results are shown in Table 1.

  As is clear from the results shown in Table 1, Samples 1 to 3 which are the products of the present invention exhibited excellent effects in both feeling of use and storage stability (low temperature to high temperature). On the other hand, the blending ratio (mass ratio) of the component (b) to the component (c) is out of the range of the present invention. . Moreover, in place of component (b), POE hydrogenated castor oil was used, and sample 7 in which this POE hydrogenated castor oil and component (c) were combined resulted in poor long-term storage stability.

(Example 2: Drug component residual ratio measurement test)
Among the samples shown in Table 1 above, the following samples:
Sample 1: (b) component 0.5% by mass, (c) component 0.7% by mass, sample 4: (b) component 1.0% by mass, (c) component 0.7% by mass, sample 6: (b) 0% by mass of component, (c) 0.7% by mass of component, each was placed in a polyethylene container and stored at 0 ° C for 1 month and at 50 ° C for 1 month. About the residual rate of a chemical | medical agent component, the measurement test (acceleration test) was done according to the liquid chromatograph method of the general test method of a Japanese pharmacopoeia (n = 3, each sample 3 point measurement). The results are shown in Tables 2-3. Table 2 shows the measured values (drug component residual ratio), and Table 3 is a processed version of Table 2. The residual ratio after storage at 0 ° C for 1 month is taken as 100%, which is 1 month at 50 ° C. The percentage of remaining drug components after storage for a while is shown.

  According to the Pharmaceutical Affairs Law, 90.0 to 110.0% of the indicated amount has drug stability. As is clear from the results in Tables 2 and 3, it was confirmed that in any of Samples 6, 1 and 4, the drug residual rate was high even after 1 month at 50 ° C., and the drug stability was excellent. In addition, it was found that the residual ratio was high for both tocopherol acetate and vitamin A oil, which are optional additives, and oil-soluble vitamins.

(Summary)
From the results of Tables 1 and 2-3, the drug component residual rate of the component (a) can be achieved by blending the component (c), but in order to achieve both the usability effect and the formulation storage stability effect, It turned out that it is necessary to mix | blend (b) component and (c) component by the ratio of (b) / (c) = 0.1-1.3.

The formulation examples are further shown below.
[Formulation Formulation Example 1]
(Mixed component) (mass%)
Purified water Residual glycerin 10
1,3-butylene glycol 10
Sodium hyaluronate 0.001
Carboxyvinyl polymer 0.15
Polyvinyl alcohol 0.4
Xanthan gum 0.03
POE (20) behenyl ether 0.75
Glyceryl monostearate 0.75
Ufenamart 1
Vitamin A oil 0.2
Stearyl alcohol 2
Behenyl alcohol 2
White petrolatum 2
Microcrystalline wax 1
Isopropyl myristate 12
Liquid paraffin 5
Potassium hydroxide 0.1
Phenoxyethanol 0.3
Methyl paraoxybenzoate 0.2

[Formulation Formulation Example 2]
(Mixed component) (mass%)
Purified water Residual glycerin 10
Dipropylene glycol 5
1,3-butylene glycol 5
Winged bean extract (dry mass) 0.001
Carboxyvinyl polymer 0.15
Polyvinyl alcohol 0.4
POE (20) behenyl ether 0.7
Glycerol monostearate 0.5
Ufenamart 3
Tocopherol acetate 2
Cetyl alcohol 2
Stearyl alcohol 2
White petrolatum 2
Microcrystalline wax 1
Glycerin triisooctanoate 10
Tocopherol acetate 0.05
Liquid paraffin 5
Dimethylpolysiloxane 2
Potassium hydroxide 0.1
Citric acid hydrate 0.02
Methyl paraoxybenzoate 0.2

[Formulation Formulation Example 3]
(Mixed component) (mass%)
Purified water Residual glycerin 5
1,3-butylene glycol 7
Macrogol 1000 2
Tranexamic acid 2
Carboxyvinyl polymer 0.25
Polyvinyl alcohol 0.3
POE (20) behenyl ether 0.3
Glycerol monostearate 0.2
Ufenamart 4
Vitamin A oil 0.5
Tocopherol acetate 0.5
Stearyl alcohol 0.5
Behenyl alcohol 0.5
White petrolatum 0.5
Isopropyl myristate 5
Light liquid paraffin 5
Methyl paraoxybenzoate 0.2

[Formulation Formulation Example 4]
(Mixed component) (mass%)
Purified water Residual glycerin 12
Dipropylene glycol 5
Yuzu seed extract (dry mass) 0.001
Potassium 4-methoxysalicylate 0.5
Carboxyvinyl polymer 0.35
Polyvinyl alcohol 0.4
Xanthan gum 0.05
POE (20) behenyl ether 1
Glycerol monostearate 0.1
Ufenamart 2
Vitamin A oil 0.2
Tocopherol acetate 0.5
Stearyl alcohol 0.7
Behenyl alcohol 0.5
White petrolatum 0.5
Hardened oil 1
Isopropyl myristate 5
Liquid paraffin 5
Potassium hydroxide 0.1
Methyl paraoxybenzoate 0.2

[Formulation prescription example 5]
(Mixed component) (mass%)
Purified water Residual glycerin 10
1,3-butylene glycol 5
Vitamin A acetate 0.5
Macrogol 1500 2
Carboxyvinyl polymer 0.2
Polyvinyl alcohol 0.4
Xanthan gum 0.05
Ufenamart 5
POE (20) behenyl ether 1.5
Glycerol monostearate 1.5
Behenyl alcohol 3
White petrolatum 2
Microcrystalline wax 1
Isopropyl myristate 12
Light liquid paraffin 5
Dimethylpolysiloxane 2
Potassium hydroxide 0.1
Methyl paraoxybenzoate 0.2

  According to the present invention, a creamy external pharmaceutical emulsion emulsified with a stable blend of ufenamate, excellent in feeling of use (no stickiness, firmness and plumpness) and excellent in long-term storage stability in a wide temperature range from low to high temperatures. A formulation is provided.

Claims (7)

  (A) Ufenamate, (b) glycerin fatty acid monoester, (c) polyoxyethylene (2 to 50 mol addition) alkyl ether, (b) component / (c) component = 0.1 to 1.3 A skin emulsified pharmaceutical preparation containing a ratio of (mass ratio).   The pharmaceutical emulsified preparation for external use according to claim 1, further comprising (d) a solid to semi-solid oil containing a higher aliphatic alcohol.   The pharmaceutical emulsified preparation for external use according to claim 1 or 2, further comprising (e) a water-soluble polymer mainly composed of polyvinyl alcohol.   The pharmaceutical emulsion preparation for external use according to claim 3, further comprising a carboxyvinyl polymer in the component (e).     The pharmaceutical emulsion formulation for external use according to claim 3 or 4, further comprising a polysaccharide water-soluble polymer in the component (e).   Furthermore, the pharmaceutical emulsion formulation for skin external use in any one of Claims 1-5 containing vitamin A oil and / or tocopherol acetate.   The pharmaceutical emulsion preparation for external use according to claim 1, which is an oil-in-water emulsion pharmaceutical preparation for external use on skin.