JP5556339B2 - Acne preparation for external use - Google Patents

Description

  The present invention relates to an external preparation composition for acne.

External preparations for the purpose of sterilizing acne and fingers include creams, emulsions, liquids, etc. Among them, liquids are widely used because they can be widely applied and have little stickiness.
By the way, isopropyl methylphenol (hereinafter sometimes abbreviated as IPMP) among the bactericidal components has a broad antibacterial spectrum compared to a cationic bactericidal component such as benzalkonium chloride. It is used in medicines and acne treatments.
However, since IPMP has extremely low solubility in water, it has been conventionally solubilized by blending various surfactants or blending ethanol. For example, the liquid formulation proposed as a composition for oral cavity has been solubilized only with a surfactant having a high HLB since the blending amount of IPMP is small. However, when an effective amount in acne treatment is blended, it precipitates at a low temperature. There was a problem that. Although the precipitation of IPMP is improved by adding ethanol as a solubilizing agent, if ethanol is used as a blending amount necessary for solubilization, a high concentration of ethanol causes skin irritation during and after use. Therefore, there has been a demand for an external preparation in which IPMP is solubilized while suppressing the amount of use.
In addition, the following are mentioned as prior art documents relevant to the present invention.

JP 2009-149568 A JP 2009-184951 A

  The present invention has been made in view of the above circumstances, and is excellent in appearance stability at low temperature without adding a large amount of ethanol to a topical composition for acne containing isopropylmethylphenol as a bactericidal component, and skin irritation. It aims at providing the external preparation composition for acne which suppressed feeling.

  As a result of intensive studies to achieve the above object, the inventors of the present invention have formulated ethanol at a high concentration to precipitate IPMP that appears at the time of freezing and restoration, which cannot be solved only by adding a surfactant as a solubilizing agent for IPMP. The present invention finds that an external preparation composition for acne can be obtained by blending 1,3-butylene glycol and glycerin at a specific ratio without reducing the skin irritation. It came to an eggplant.

Accordingly, the present invention provides the following external preparation composition for acne.
Claim 1:
(A) Isopropylmethylphenol 0.2-1.0 mass%, (B) 1,3-butylene glycol, (C) glycerin, and (D) HLB15 or more nonionic surfactant,
The content mass ratio of the total amount of the components (B) and (C) to the component (A) represented by {(B) + (C)} / (A) is 40 or more, and (B) / (C) The content ratio of the component (B) to the component (C) represented by the formula is in the range of 1.5 to 3.5, and the content ratio of (E) ethanol is 0 to 10 % by mass. An external preparation composition for acne.
Claim 2:
The external preparation composition for acne according to claim 1, further comprising (F) salicylic acid and having a pH in the range of 2 to 5.

  ADVANTAGE OF THE INVENTION According to this invention, the external preparation composition for acne which has high external appearance stability also at low temperature, and also the skin irritation was suppressed can be provided.

The composition of the present invention comprises (A) 0.2 to 1.0% by mass of isopropylmethylphenol, (B) 1,3-butylene glycol, (C) glycerin, and (D) a nonionic surfactant having an HLB of 15 or more. The content mass ratio of the total amount of (B) and (C) component to (A) component represented by {(B) + (C)} / (A) is 40 or more, ) / (C) The content mass ratio of the (B) component to the (C) component is in the range of 1.5 to 3.5, and (E) the ethanol content is 0 to 10 mass %. It is an external preparation composition for acne.

[(A) Isopropylmethylphenol (IPMP)]
Isopropylmethylphenol is an active ingredient of the composition for external use for acne of the present invention, and is blended as a bactericidal agent. Isopropylmethylphenol is an effective bactericidal agent for diseases that may be exacerbated by bacteria such as eczema, dermatitis, acne, and fungi, and is particularly effective in treating acne.

  The blending amount of the component (A) effective for acne treatment is preferably 0.2 to 1.0% by mass, more preferably 0.3 to 1.0% by mass, based on the total amount of the external preparation for acne. More preferably, it is 3 to 0.8% by mass. If it is less than 0.2% by mass, the bactericidal effect becomes weak, and if it exceeds 1.0% by mass, skin irritation or the like occurs. If it is 0.2-1.0 mass%, the bactericidal power effective in acne treatment can be obtained.

[(B) 1,3-butylene glycol]
1,3-butylene glycol is blended as an IPMP precipitation preventing, solubilizing agent and wetting agent. 1,3-Butylene glycol is a liquid component that has a moisturizing effect, antibacterial action, and solubility, and is incorporated into various pharmaceuticals and cosmetics such as emulsions, creams, and ointments as moisturizing agents, solvents, viscosity reducing agents, and fragrances Is done. When the product of the present invention falls under the category of a pharmaceutical product, a product that conforms to the pharmaceutical additive standard is used. When the product belongs to a quasi-drug or cosmetic, a product that conforms to the quasi-drug raw material standard is used.

  (B) As for the compounding quantity of a component, 5-40 mass% is preferable with respect to the whole external preparation composition for acne of this invention, More preferably, it is 8-30 mass%. If the blending amount of the component (B) is too small, isopropylmethylphenol may be easily precipitated at a low temperature, and if it is too large, stickiness may be felt after application to the skin.

[(C) Glycerin]
Glycerin is blended as an IPMP precipitation preventing, solubilizing agent and wetting agent. Glycerin is a trivalent alcohol that has a very low toxicity and is a liquid component having hygroscopicity. It has a moisturizing effect and is mainly formulated as a moisturizing / wetting agent and water retaining agent in pharmaceuticals and cosmetics, and also as a viscosity reducing agent, skin protecting agent, solvent and the like. When the product of the present invention falls under the category of a pharmaceutical product, a product that conforms to the pharmaceutical additive standard is used. When the product belongs to a quasi-drug or cosmetic, a product that conforms to the quasi-drug raw material standard is used.

  (C) As for the compounding quantity of a component, 2-20 mass% is preferable with respect to the whole external preparation composition for acne of this invention, More preferably, it is 3.5-15 mass%. If the blending amount of the component (B) is too small, isopropylmethylphenol may be easily precipitated at a low temperature, and if it is too large, stickiness may be felt after application to the skin.

  Here, the total content of the components (B) and (C) is preferably 8 to 50% by mass, more preferably 12 to 45% by mass, and still more preferably 15 to 15%, based on the total composition for external use for acne of the present invention. 45% by mass.

Moreover, the mass ratio of (B) and (C) component to (A) component represented by {(B) + (C)} / (A) is 40 or more, preferably 40 to 300, More preferably, it is the range of 40-230. If it is less than 40, the low temperature stability of the component (A) deteriorates, and if it is too much, stickiness may occur after use.
Further, the mass ratio of the component (B) to the component (C) represented by (B) / (C) is in the range of 1.5 to 3.5, preferably 1.5 to 3.0. is there. Even if it is less than 1.5 or exceeds 3.5, the low temperature stability of the component (A) deteriorates.

[(D) Nonionic surfactant having HLB of 15 or more]
A nonionic surfactant is mix | blended as a solubilizer of IPMP. The nonionic surfactant used in the present invention needs to have an HLB value of 15 or more, preferably 17 to 20. If the HLB value is too low, the component (A) IPMP cannot be sufficiently solubilized.
Examples of such nonionic surfactants include polyoxyethylene (EO 10-60) alkyl (carbon number 12-22) ether, polyoxyethylene (EO 10-20) polyoxypropylene (PO4-30) alkyl (carbon). (Equation 12-16) Ether type nonionic surfactant such as ether, polyoxyethylene (EO20) sorbitan fatty acid (carbon number 12-18) ester, polyoxyethylene (EO6-60) sorbite fatty acid (carbon number 12-18) ) Ester-type nonionic surfactants such as esters, polyoxyethylene (EO 80-100) hydrogenated castor oil, polyethylene glycol (EO 25-55) fatty acid (carbon number 12-18) ester, and the like. Among these, polyoxyethylene (EO 10-60) alkyl (carbon number 12-22) ether, polyoxyethylene (EO 80-100) hydrogenated castor oil, polyethylene glycol (EO 25-55) fatty acid (carbon number 12-18) Esters are preferred. More specifically, polyoxyethylene (21) lauryl ether, polyoxyethylene (25) lauryl ether, polyoxyethylene (15) cetyl ether, polyoxyethylene (23) cetyl ether, polyoxyethylene (30) cetyl ether , Polyoxyethylene (40) cetyl ether, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (20) behenyl ether, polyoxyethylene (30) behenyl ether, polyoxyethylene ( 80) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil, polyethylene glycol monostearate (40EO), polyethylene glycol monostearate (55EO), polyoxyethylene (20) poly Examples thereof include xylpropylene (4) cetyl ether, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monooleate, and among these, in particular, polyoxyethylene (21) lauryl Ether, polyoxyethylene (25) lauryl ether, polyoxyethylene (23) cetyl ether, polyoxyethylene (30) cetyl ether, polyoxyethylene (20) oleyl ether, polyoxyethylene (20) stearyl ether, polyoxyethylene (30) Behenyl ether, polyethylene glycol monostearate (40EO), etc. are more effective.
These nonionic surfactants can be used singly or in appropriate combination of two or more. In addition, even if it is a nonionic surfactant having an HLB value of less than 15 alone, the nonionic surfactant exemplified above is used in combination so that the HLB value as a whole surfactant is 15 or more. Can be used with adjustment.

  (D) As for the compounding quantity of a component, 0.5-5.0 mass% is preferable with respect to the whole external preparation composition for acne, and 1.3-3.0 mass% is more preferable. If it is less than 0.5% by mass, component (A) may not be sufficiently solubilized, and if it exceeds 5.0% by mass, skin irritation or the like may occur.

[(E) Ethanol]
When ethanol is blended in the external preparation composition for acne of the present invention, it is blended as a solubilizer for IPMP. The content of ethanol acne external preparation composition of the present invention is 10 wt% or less (0-1 0% by weight), preferably 8 wt% or less, particularly 6 wt% or less, and a particularly 4 wt% or less, By adding a small amount of ethanol, the low temperature stability can be further improved while maintaining a good feeling of use. When the added amount of ethanol exceeds 10% by mass, skin irritation or the like occurs. Ethanol can be used regardless of whether it is denatured or undenatured. However, if the product of the present invention falls under the category of a pharmaceutical product, one that conforms to the Japanese Pharmacopoeia can be used. Use quasi-material standards. Specifically, anhydrous ethanol manufactured by Gansu Chemical Industry Co., Ltd., general alcohol 95 degree synthetic unmodified by Mitsubishi Chemical Co., Ltd., government specified ethanol manufactured by Shinwa Alcohol Co., Ltd., etc. can be suitably used. .

[(F) salicylic acid]
Salicylic acid can be blended in the composition of the present invention. Salicylic acid is blended as a drug having an action of peeling the cornified stratum corneum. It also has bactericidal action and is effective for acne treatment. Although the composition of the present invention is excellent in low-temperature stability, even if salicylic acid is further added, even if the stability of IPMP is lowered and precipitated, the acne treatment effect of the external preparation for acne of the present invention is maintained. Can do. Conventionally, sulfur, resorcin, benzoyl peroxide, salicylic acid, and the like have been used as a stratum corneum peeling / dissolving agent, and especially salicylic acid has a bactericidal action, an anti-inflammatory action, etc. in addition to a stratum corneum peeling / dissolving action. In double-blind clinical trials, the therapeutic effect on acne vulgaris has been confirmed and it is widely used as an active ingredient in acne treatments.
(F) Although the compounding quantity of a component is not restrict | limited in particular, if the objective of this invention is considered, 0.1-10 mass% is preferable with respect to the whole external preparation composition for acne of this invention, 0.1-2 mass% is more preferable, and 0.2-1.0 mass% is especially preferable. If the concentration of the component (F) is too low, it may be difficult to obtain a sufficient therapeutic effect.

[Other ingredients]
The external preparation composition for acne of the present invention includes various optional components that can be blended in the external preparation composition for acne (liquid agent) in addition to the above components, such as a polymer compound, a pH adjuster, a chelating agent, an antiseptic, a fragrance, A pigment | dye etc. can be contained in the range which does not impair the effect of this invention. These may be used alone or in appropriate combination of two or more.

  The polymer compound is preferably a polymer compound that is soluble in water or a mixed solvent system of lower alcohol / water, such as cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carmellose, croscarmellose, methylcellulose, Modified starch such as partially pregelatinized starch, polyvinyl alcohol, polyvinylpyrrolidone, crospovidone, polyethylene glycol, xanthan gum, carrageenan, sodium alginate, gum arabic, guar gum, locust bean gum, pullulan, gelatin, carboxyvinyl polymer, acrylic acid / methacrylic acid Examples thereof include alkyl copolymers and sodium polyacrylate. Although the compounding quantity of a high molecular compound is suitably selected by the setting viscosity of the external preparation composition for acne, 0.01-10 mass% is preferable in an external preparation composition for acne, More preferably, it is 0.05-5. % By mass.

  pH adjusters include inorganic acids such as hydrochloric acid, phosphoric acid and boric acid, organic acids such as lactic acid, tartaric acid and citric acid, sodium hydroxide, potassium hydroxide, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine And various amines such as triisopropanolamine and tromethamine, phosphates such as potassium hydrogenphosphate and sodium hydrogenphosphate, and organic salts such as sodium citrate and sodium lactate. Diisopropanolamine, triisopropanolamine, and triethanolamine are preferable because pH stability is particularly good when an acidic drug is used. The blending amount of the pH adjuster can be appropriately selected depending on the set pH.

  Examples of the chelating agent include pyrophosphate, hexametaphosphate, gluconate, edetate and the like. The compounding amount of the chelating agent is preferably 0.001 to 5 mass%, more preferably 0.01 to 5 mass% in the external preparation composition for acne.

  Examples of the preservative include dibutylhydroxytoluene, benzoic acids, parabens, benzalkonium chloride, benzethonium chloride, sorbic acid and its salts, boric acid, borax and the like. Preferably dibutylhydroxytoluene, citric acid and its salts are used. The compounding amount of the preservative is preferably 0.005 to 5 mass%, more preferably 0.01 to 1 mass% in the external preparation composition for acne.

  As the pigment, any pigment that can be used in external preparations (cosmetics, pharmaceuticals) such as an acid dye, a basic dye, an oxidation dye, and a pigment can be arbitrarily used. As the fragrance, a natural fragrance or a synthetic fragrance can be used without any particular limitation. For example, examples of natural flavors include vegetable flavors such as peppermint oil, spearmint oil, jasmine oil, lemon oil, orange oil, lime oil, mandarin oil, rose oil, and rosemary oil. Synthetic fragrances include monoterpenes, diterpenes, sesquiterpenes, etc., specifically geraniol, linalool, citronellol, nerol, limonene, pinene, camphene, citral, citronellal, cineole, curcumene, hinokic acid, hinokiol, phytol, etc. Is mentioned. The blending amount of the pigment and the fragrance is preferably 0.0001 to 5% by mass, more preferably 0.0001 to 1% by mass in the external preparation composition for acne.

[PH]
The pH of the composition for external use for acne of the present invention is more preferably 2 to 5, and further preferably 2 to 4, from the viewpoint of stratum corneum peeling, dissolving action and skin irritation when (F) salicylic acid is blended. If the pH is set to an acidic range from pH 2, skin irritation may be caused, and if the pH is set to an alkaline range from pH 5, the effect of salicylic acid may be hardly exhibited. In addition, in this invention, pH is the value measured by the Japanese Pharmacopoeia general test method and the pH measurement method.

[viscosity]
The external preparation composition for acne of the present invention is preferably a liquid preparation such as a lotion preparation, and the content of a solvent such as water is preferably 30 to 90% by mass of the entire external preparation composition for acne. In this case, the viscosity of the external preparation composition for acne of the present invention is preferably 0.5 to 50,000 mPa · s, more preferably 0.5 to 1,000 mPa · s, and still more preferably 0.5 to 50,000 mPa · s. 500 mPa · s. If the viscosity is too low, the usability may be deteriorated such as dripping, and if it is too high, the liquid may not be easily discharged from the bottle or may not be easily extended to the affected area. In addition, in this invention, a viscosity is a value in 25 degreeC measured according to the Japanese Pharmacopoeia general test method viscosity measuring method and the 2nd method rotational viscometer method.

[Production method]
As a method for producing an external preparation composition for acne of the present invention, it can be produced according to the Japanese Pharmacopoeia General Rules for Lotions. (A) IPMP is dissolved in (D) a surfactant, and (B). It is preferable to add and dissolve in a liquid in which 1,3-butylene glycol, (C) glycerin and purified water are mixed. The dissolved solution is preferably filtered with a membrane filter (eg, OMNIPORE membrane filter JHWP04700 manufactured by MILLIPORE Co., Ltd.). When (E) ethanol is blended, it is preferably dissolved together with the components (A) and (D). Furthermore, when (F) salicylic acid is blended, it is also dissolved with the components (A) and (D). Is preferred.

  The container filled with the external preparation composition for acne of the present invention can be any container (bottle, can, jar, etc.), and the material thereof is polyethylene terephthalate (PET), polypropylene (PP), polyethylene ( It is preferably selected from high density polyethylene (HDPE, low density polyethylene: LDPE), glass, resin such as polystyrene and eval, and metal such as aluminum, and more preferably PET, PP, and glass.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 27, Comparative Examples 1 to 9]
The composition for external use for acne was prepared by the following method with the mixture ratio described in Tables 2-5.
<Preparation method>
The amounts of the blending components described in Tables 2 to 5 were taken up. (C) Glycerin, (B) 1,3-butylene glycol, and purified water are mixed and dissolved uniformly. Separately, (A) isopropylmethylphenol and (D) surfactant are uniformly dissolved. Stir until homogeneous. The mixture was filtered with an OMNIPORE membrane filter JHWP04700 manufactured by MILLIPORE Co., Ltd. to obtain an external preparation composition for acne of the present invention.

<-5 ° C stability>
50 mL of the prepared sample was put in a transparent glass bottle, stored at −5 ° C. for 1 month, transferred to 5 ° C., and evaluated for appearance after half a day according to the following evaluation criteria. The sample in which precipitation was slightly observed at 5 ° C. was transferred to room temperature (15 to 25 ° C., hereinafter the same), and the appearance was evaluated according to the following evaluation criteria after half a day. ○ The above was accepted. The results are also shown in Tables 2-5.
Evaluation criteria ◎: Colorless and transparent liquid equivalent to the product immediately after manufacture ○: Slight precipitation is observed at the bottom of the bottle, but the precipitate disappears when moved to room temperature (no problem)
Δ: Slight precipitation is observed at the bottom of the bottle, and the precipitation does not disappear even when moved to room temperature. ×: State where precipitation is clearly seen at the bottom of the bottle.

<Freezing and restoring properties>
50 mL of the prepared sample was put in a transparent glass bottle, stored at −20 ° C. for 24 hours, and then stored at 5 ° C. for 24 hours. After repeating this 6 times, the appearance at 5 ° C. or at normal temperature was evaluated according to the following evaluation criteria. ○ The above was accepted. The results are also shown in Tables 2-5.
Evaluation criteria ◎: Colorless and transparent liquid equivalent to the product immediately after production at 5 ° C ○: Slight precipitation is observed at the bottom of the bottle at 5 ° C, but the precipitate disappears when moved to room temperature (no problem)
Δ: Slight precipitation is observed at the bottom of the bottle at 5 ° C, and the precipitate does not disappear even when moved to room temperature. ×: State where precipitation is observed at the bottom of the bottle at 5 ° C and room temperature.

<Skin irritation>
The feeling of use was evaluated based on skin irritation during and after use.
An appropriate amount (about 2 mL) of a sample was put on a commercially available cotton (Beauty Up Cotton: manufactured by Shiseido Co., Ltd., 5.5 × 7 cm (actual measurement)) and pressed against the cheeks of the evaluation panelists (10 persons) for 3 minutes. Feeling of use and skin irritation (burning and tingling sensation) while pressing (in use), and feeling of feeling and skin irritation (burning and tingling sensation) from immediately after removal from the cheek to after 5 minutes (after use) ) Was evaluated by sensuality. The scores were scored according to the evaluation criteria, and were judged based on the following criteria table from the average value of the scores of 10 people during and after pressing. ○ The above was judged good. The results are also shown in Tables 2-5. -Indicates that the evaluation was not performed for reasons such as failure of stability.
Evaluation criteria 5 points: feel very much 4 points: feel quite 3 points: feel a little 2 points: feel a little 1 point: not feel at all

Judgment criteria

<Sterilization evaluation>
In order to verify the effect on acne-causing bacteria, the bactericidal action was evaluated.
As a method for measuring the bactericidal action, the minimum growth inhibitory concentration (MIC) for acne was determined by a liquid medium dilution method. That is, it is diluted 1 to 64 times with GAM broth (modified GAM bouillon “Nissui” manufactured by Nissui Pharmaceutical Co., Ltd.). Acnes suspension (5 μL) was added, and anaerobic culture was performed at 36 ° C. for 3 days. The presence or absence of bacterial growth was observed with the naked eye. A result is shown by the dilution rate of a formulation. The larger the magnification, the lower the minimum growth inhibitory concentration, that is, the higher the bactericidal action. The-column shows-not implemented.
Sterilization evaluation was implemented about the external preparation composition for acne of Example 2,7,9-13. The results are also shown in Tables 2 and 3.

Claims (2)

(A) Isopropylmethylphenol 0.2-1.0 mass%, (B) 1,3-butylene glycol, (C) glycerin, and (D) HLB15 or more nonionic surfactant,
The content mass ratio of the total amount of the components (B) and (C) to the component (A) represented by {(B) + (C)} / (A) is 40 or more, and (B) / (C) The content ratio of the component (B) to the component (C) represented by the formula is in the range of 1.5 to 3.5, and the content ratio of (E) ethanol is 0 to 10 % by mass. An external preparation composition for acne.   The external preparation composition for acne according to claim 1, further comprising (F) salicylic acid and having a pH in the range of 2 to 5.