JP2009167139A - External use composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external use composition suppressing the growth of Candida fungi in skin or a mucous membrane, and having excellent safety without problems of toxicity and irritancy. <P>SOLUTION: The external composition for suppressing the growth of the Candida fungi in the skin or the mucous membrane is characterized by comprising one or more kinds selected from among the group consisting of sorbic acid, a sorbic acid salt, benzoic acid, and a benzoic acid salt, and propylene glycol. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a composition for external use. Specifically, the present invention relates to an external composition capable of suppressing the growth of Candida bacteria on the skin and mucous membranes.

Candida (Candida) bacteria, in one fungal constituting the existing normal flora in human skin and mucous membranes, usually present in keeping the balance with other flora, to exhibit pathogenicity Absent. However, due to factors such as decreased immunity due to cancer, diabetes, immune deficiency, stress, etc., overdose of drugs such as anticancer drugs, antibiotics, steroids, immunosuppressants, deterioration of hygiene, etc. If the balance is lost and Candida bacteria grow excessively, candidiasis is caused. Candida albicans is a typical causative agent of candidiasis. Candidiasis is broadly divided into superficial candidiasis that develops on the skin or the mucosa adjacent to the skin (oral cavity, vagina, etc.) and deep candidiasis that affects deep organs. And mucosal candidiasis. There are several different types of cutaneous candidiasis depending on the site and age of infection, such as candidal interstitial rash, candidal interdigital erosion, candidal onychonitis, and infantile parasite erythema. The majority of mucosal candidiasis occurs in the oral cavity or vagina and are called oral candidiasis and vulvovaginal candidiasis, respectively. Superficial candidiasis is one of the most frequent mycoses, and is known to cause health problems such as itching and pain, and aspiration pneumonia. On the other hand, deep candidiasis shows severe symptoms with lesions extending to the esophagus, stomach, small intestine, large intestine, urinary tract, lung, kidney, heart, liver, spleen, and brain, but there are few cases.

  Treatment of superficial candidiasis is based on topical treatment with external drugs. Conventionally, imidazole antibacterial agents (antifungal agents) have been widely used, and many pharmaceutical formulations have been reported to enhance their effects. . For example, Patent Document 1 discloses that by using an antibacterial agent and a peripheral vasodilator in combination, the efficacy of the antibacterial agent can be enhanced and the fungus can be efficiently negated in a short time. However, imidazole antibacterial agents may give strong irritation to skin and mucous membranes, and are not suitable for prophylactic use in addition to limited application sites.

  As a composition for oral cavity that can inhibit the growth of Candida in the oral cavity and prevent stomatitis caused by this, Patent Document 2 uses sorbic acid or a salt thereof and benzoic acid or a salt in combination at a specific ratio. Is disclosed. Here, sorbic acids and benzoic acids are compounds widely used as preservatives (preservatives). However, in order to obtain a sufficient anti-Candida activity with the above components, it is necessary to make the liquid nature acidic, and there is a possibility of promoting tooth decalcification as an oral composition, and there are problems of palatability. In addition, diversion to other than the oral cavity was difficult in terms of acid stimulation.

  By the way, in recent years, consumer interest in human safety has increased rapidly, and the demand for “human-friendly” products has increased. Preservatives are no exception, especially parabens (which are most frequently used as safe and effective preservatives) because of problems such as irritation and allergies to some sensitive users. There is a tendency to refrain from using or to reduce the amount used. Under such circumstances, 1,2-alkanediol used as a moisturizer, solvent, etc. has its own antibacterial action, and further, in combination with conventional preservatives, synergizes the antibacterial action of the preservative. It has been reported that the amount of preservative used can be significantly reduced by increasing the amount.

For example, Patent Document 3 discloses a composition for external use comprising 1,2-pentanediol and 2-phenoxyethanol as preservatives.
Patent Document 4 includes 1,2-alkanediol having 4 to 10 carbon atoms, preferably one or more of 1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol. Antiseptic disinfectant; one or more of Photosensitive Element 201 (Pionine), benzoic acid and its salt, phenoxyethanol, 4-isopropyl-3-methylphenol, and one or more of the 1,2-alkanediols And an antiseptic disinfectant formed by combining the antiseptic disinfectant and a human body composition comprising the antiseptic disinfectant.
Patent Document 5 discloses an antiseptic fungicide formed by combining one or more parabens and one or more of 1,2-alkanediols similar to Patent Document 4; and A cosmetic composition obtained by blending is disclosed.
Patent Document 6 discloses a cosmetic comprising a cosmetic moisturizing bacteriostatic agent comprising 1,2-octanediol; and the cosmetic moisturizing bacteriostatic agent.

  However, the compositions described in Patent Documents 3 to 6 use 1,2-alkanediol in order to prevent the composition itself from being spoiled due to microbial contamination, and in the skin and mucous membrane to which the composition is applied. It did not inhibit the growth of microorganisms. In addition, the antibacterial action of 1,2-alkanediol is against so-called general bacteria such as Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and the action against fungus Candida has not been sufficiently studied . Furthermore, when 1,2-alkanediol is used alone as a preservative, a high blending amount is required, and there is a problem of irritation. In particular, 1,2-alkanediol having a high antibacterial action (generally, the higher the carbon number, the higher the antibacterial action) has a problem that the application site is limited because of its high toxicity to the human body. In these respects, the compositions described in Patent Documents 3 to 6 are not suitable for compositions intended to suppress the growth of Candida bacteria on the skin and mucous membranes.

  Therefore, there is still a need for the development of a composition for external use that has the effect of suppressing the growth of Candida bacteria on the skin and mucous membranes, has no toxicity and irritation problems, and is excellent in safety.

Japanese Patent Laid-Open No. 7-233088 JP-A-5-262631 JP-A-10-53510 Japanese Patent Laid-Open No. 11-322591 JP 11-310506 A JP 2001-48720 A

  The present invention was made in order to solve the above-mentioned problems in the prior art, and the object of the present invention is a composition for external use that can suppress the growth of Candida bacteria on the skin and mucous membrane, and is toxic. And providing a composition for external use having no safety and irritation problems and excellent in safety.

  As a result of repeated studies to solve the above problems, the present inventors have heretofore been used from the group consisting of sorbic acid, sorbic acid salt, benzoic acid, and benzoic acid salt that have been used as preservatives and have been confirmed to be safe. A composition comprising a combination of one or more selected with propylene glycol, which has been conventionally used as a humectant and has been confirmed to be safe, can proliferate Candida in a wide pH range from acidic to neutral. It has been found that it can be suppressed, and the present invention has been completed.

That is, the present invention is a composition for external use for suppressing the growth of Candida in skin and mucous membranes, and is one or more selected from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate And propylene glycol. The composition for external use characterized by the above-mentioned.
In the external composition, the total amount of sorbic acid and sorbate is preferably 0.5% by weight or less, and the amount of benzoic acid is preferably 0.2% by weight or less. The total amount of the acid salt is preferably 1.0% by weight or less, and at least one amount selected from the group consisting of sorbic acid, sorbic acid salt, benzoic acid, and benzoic acid salt The total amount of is preferably 0.01 to 1.5% by weight. Moreover, it is preferable that the compounding quantity of propylene glycol is 0.5 to 15 weight%.
Furthermore, the blending ratio of one or more selected from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate and propylene glycol is 1: 1 to 1: 200 by weight. preferable.
The external composition preferably contains at least one selected from the group consisting of potassium sorbate and sodium benzoate and propylene glycol.
The pH of the external composition is preferably 4.0 to 7.5.

  ADVANTAGE OF THE INVENTION According to this invention, the composition for external use which can suppress the proliferation of Candida in skin and mucous membrane is provided. The composition of the present invention has no problem of toxicity and irritation, is excellent in safety, and is useful for prevention of superficial candidiasis or improvement of symptoms thereof.

  The composition for external use of the present invention is a composition for external use for suppressing the growth of Candida in the skin and mucous membrane, and is selected from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate 1 It contains at least seeds and propylene glycol (also called 1,2-propanediol or 1,2-dihydroxypropane) as essential components. It is known that 1,2-alkanediol has an antibacterial effect on general bacteria and can be synergistically enhanced by combining it with an antiseptic, but it has a low carbon number of 3 and high It is possible to effectively increase the anti-Candida activity of sorbic acid and benzoic acid by combining propylene glycol, which has no anti-Candida activity, with sorbic acid or benzoic acid, and it can range from acidic to neutral. It was completely unexpected to show an excellent anti-Candida activity in a wide pH range. Although the mechanism is not clear, the high hydrophilicity and emulsification of propylene glycol cause dehydration and decreased water activity of Candida cells and protein denaturation. As a result, the anti-Candida activity of sorbic acids and benzoic acids Is considered to be effective.

  In the present invention, the composition for external use is a concept encompassing generally all compositions used for external use, and particularly refers to a composition applied to the skin or mucous membrane (oral cavity, vagina, etc.) adjacent to the skin. The composition for external use of the present invention is a composition that can inhibit the growth of Candida in the skin and mucous membranes, thereby preventing or improving the symptoms of superficial candidiasis. There are no particular restrictions on the division under the Pharmaceutical Affairs Law. Superficial candidiasis spreads to adjacent sites (for example, from the oral cavity to the respiratory tract and gastrointestinal tract, from the vulva to the urinary tract), through the mucosa, into capillaries, and secondarily to distant areas. In some cases, preventing and improving this is also significant in preventing deep candidiasis.

Candida fungi targeted by the present invention are not particularly limited, and refer to all fungi belonging to the genus Candida , for example, Candida albicans , Candida tropicalis , Candida · Parashiroshisu (Candida parapsilosis), Candida glabrata (Candida grabrata), Candida Girierumonjii (Candida guilliemondii), Candida krusei (Candida krusei) and the like. Especially, the request | requirement with respect to the growth suppression of Candida albicans which is a main causative agent of candidiasis is strong.
Moreover, the composition for external use of this invention shows the effect | action which suppresses the proliferation not only to Candida but also various microorganisms which exist in skin and mucous membrane.

Sorbic acid, sorbate, benzoic acid, and benzoate used in the present invention are widely used in pharmaceuticals, quasi drugs, cosmetics, foods, etc. as preservatives and preservatives with excellent safety. . In this invention, it mix | blends with an external composition as an anti-Candida fungi component.
Sorbic acid is a fatty acid having two unsaturated groups and is also called 2,4-hexadienoic acid. It is difficult to dissolve in water, but relatively well in ethanol. On the other hand, sorbate is easily soluble in water and is easier to use than free acid. Specific examples of the sorbate include potassium sorbate and sodium sorbate.
Benzoic acid is an aromatic carboxylic acid having a structure in which one hydrogen atom of benzene is substituted with a carboxyl group, and is also referred to as benzene carboxylic acid. It is difficult to dissolve in water, but dissolves well in ethanol and fats and oils. On the other hand, benzoates are easily soluble in water and easy to use compared to free acids. Specific examples of the benzoate include sodium benzoate and potassium benzoate.
These can be used alone or in combination of two or more. Of these, potassium sorbate or sodium benzoate is preferable in terms of ease of use and safety to the human body.
Note that the anti-Candida activity of sorbic acids and benzoic acids depends on pH, and when it is acidic, it exhibits a good effect, but when it becomes close to neutral, it significantly decreases. In the present invention, by combining with propylene glycol, it is possible to suppress the decrease in anti-Candida activity observed when used alone.

  The compounding quantity of the said component in an external composition is an effective quantity which suppresses the growth of Candida in skin and mucous membrane. Although the specific blending amount varies depending on the form of the composition for external use and the type of other components, it is necessary to set the blending amount below the maximum blending amount permitted by the Pharmaceutical Affairs Law. For example, the maximum blending amount of sorbic acid and sorbate is 0.5% by weight as a total amount, the maximum blending amount of benzoic acid is 0.2% by weight, and the maximum blending amount of benzoate is 1 as the total amount. 0.0% by weight. When (A) sorbic acid and / or sorbate, (B) benzoic acid, and (C) benzoate are used in combination, the blending amounts of (A), (B), and (C) are specified. However, in the present invention, the total amount of sorbic acid, sorbate, benzoic acid, and benzoate is 1.5% by weight or less. Preferably there is. If the total amount exceeds 1.5% by weight, irritation to the skin and mucous membrane may be a problem in some sensitive users. On the other hand, as a lower limit, it is preferable that the total amount of blending is 0.01% by weight or more. If the total amount is less than 0.01% by weight, the effect of suppressing the growth of Candida bacteria on the skin and mucous membrane may not be sufficiently obtained. As for the total amount of a compounding quantity, it is more preferable that it is 0.1 to 1.0 weight%.

  Propylene glycol used in the present invention is an alcohol having two hydrophilic hydroxyl groups and is a water-soluble, colorless and odorless slightly viscous liquid. In addition to excellent properties as a solvent, it has a wetting action, a moisturizing action, an antiseptic action, an emulsifying action and the like. In addition, it has low toxicity to the human body and low irritation to the skin and mucous membranes. Taking advantage of these features, it is widely used as a moisturizing agent and solvent mainly in pharmaceuticals, quasi drugs, cosmetics, foods and the like. In this invention, it mix | blends with the composition for external use as a component which strengthens the anti-Candida fungi action of sorbic acid and benzoic acid. Moreover, by mix | blending propylene glycol, the composition for external use of this invention becomes the thing excellent also in the effect | action which moisturizes and smoothes skin and a mucous membrane.

  The blending amount of propylene glycol in the composition for external use is an effective amount for enhancing the anti-Candida activity of sorbic acids and benzoic acids. Although the specific blending amount varies depending on the form of the composition for external use and the type of other components, it is generally preferably 0.5 to 15% by weight, more preferably 1 to 10% by weight, More preferably, it is 10% by weight. If the blending amount is less than 0.5% by weight, the effect of enhancing the anti-Candida activity of sorbic acids and benzoic acids may not be sufficiently obtained. If the blending amount exceeds 15% by weight, irritation to the skin and mucous membrane may be a problem or taste may be deteriorated in some sensitive users.

  Furthermore, in order to effectively obtain the effect of combining one or more selected from the group consisting of sorbic acid, sorbic acid salt, benzoic acid, and benzoic acid salt with propylene glycol, the blending ratio of both is by weight ratio. The ratio is preferably 1: 1 to 1: 200, more preferably 1: 3 to 1: 100, and still more preferably 1: 5 to 1:50. By setting the blending ratio within the above range, the anti-Candida activity can be further enhanced.

  The use form of the composition for external use is not particularly limited. For example, lotion, body lotion, emulsion, cream, hand cream, soap, face wash, hand soap, body soap, pack, shampoo, tonic, hair restorer, etc. Skin agents; oral agents such as dentifrices, mouthwashes, tongue coating cleaners, gargles, etc .; vaginal agents such as vaginal cleaners, and the like.

  The composition for external use of the present invention comprises, from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate, which are the active ingredients of the present invention, as appropriate pharmaceutically acceptable base components for formulation. It can be prepared by dissolving or mixing and dispersing at least one selected from propylene glycol. Examples of the base component include water, water-soluble polymers, fat-soluble polymers, fats and waxes, and the like.

  The dosage form of the composition for external use is not particularly limited, and may be liquid, semi-solid, or solid. Specifically, for example, liquid agents include emulsions, suspensions, aerosols, etc .; semisolid agents include ointments, plasters, creams, gels, etc .; solid agents include tablets and lozenges , Granules, capsules and the like. In addition, the composition can be spread on a suitable support to form a patch such as a poultice or a plaster.

  In the composition for external use of the present invention, known pharmaceutically acceptable ingredients can be appropriately blended in a normal dose according to the use form and dosage form. Examples of such components include thickeners / humectants, thickeners / viscosity modifiers, preservatives / preservatives, stabilizers, pH adjusters, surfactants, essential oils, fragrances, colorants, sweeteners, Examples include clarifying agents, mucosal protective agents, antibacterial agents, pharmacologically active ingredients, and inorganic salts.

  The composition for external use of the present invention has no toxicity and irritation problems and is excellent in safety. However, a mucosal protective agent may be blended in order to further improve the feeling of use. Examples of such mucosal protective agents include peptides having a protein source of sugars such as trehalose and hyaluronic acid, silk protein, milk protein and the like. These can be used alone or in combination of two or more.

  Since the composition for external use of the present invention has an excellent antibacterial action against Candida, etc., it does not necessarily require the use of other antibacterial agents. You may mix | blend. In addition, a preservative is usually added to the external composition to ensure antiseptic properties. However, the external composition of the present invention can reduce or eliminate the preservative content.

  The composition for external use of the present invention has an excellent anti-Candida activity in a wide pH range from acidic to neutral, specifically in the range of pH 2.0 to 8.0, but it is irritating to the skin and mucous membranes. In consideration, it is preferable to adjust to 4.0 to 7.5. Examples of the pH adjuster used for this purpose include citric acid, lactic acid, malic acid, phosphoric acid, tartaric acid, and salts thereof. These can be used alone or in combination of two or more.

  EXAMPLES Hereinafter, although an experiment example and an Example are shown and this invention is demonstrated concretely, this invention is not limited to these examples.

Experimental example 1
The anti-Candida activity of each component of potassium sorbate, sodium benzoate, and propylene glycol was evaluated.
Candida albicans (NBRC No. 1393) was inoculated into YM medium (Kanto Chemical Co., Inc.) and cultured at 25 ° C. for 2 days. The turbidity of the culture solution was adjusted (OD610 nm = 0.01) to obtain a test bacterial solution.

To the YM medium adjusted to pH 5.0 or 6.5, potassium sorbate, sodium benzoate, or propylene glycol was added so as to have the concentrations shown in Tables 1 to 3 to prepare a test medium. Citric acid was used as a pH adjuster. Moreover, the normal YM culture medium (pH 6.5) was used for the blank. 50 mL of the test solution of Candida albicans was inoculated into 2 mL of each medium, and the turbidity after culturing at 25 ° C. for 2 days was measured (OD610 nm). The growth rate of Candida albicans was calculated by the following formula, and the results are shown in Tables 1 to 3.
Growth rate (%) = (turbidity of test medium / turbidity of blank) × 100

  Potassium sorbate and sodium benzoate showed excellent anti-Candida activity at pH 5.0 under acidic conditions, but the anti-Candida activity was significantly reduced at pH 6.5 under neutral conditions. On the other hand, no effect of pH was observed on the anti-Candida activity of propylene glycol.

Experimental example 2
The anti-Candida fungus action when potassium sorbate or sodium benzoate and propylene glycol were combined at pH 6.5 was evaluated in the same manner as in Experimental Example 1. The results are shown in Tables 4 and 5.

  The combination of potassium sorbate or sodium benzoate and propylene glycol showed excellent anti-Candida activity even under neutral conditions.

Example 1 and Comparative Example 1
According to the composition shown in Table 6, compositions for oral cavity (gel agents) of Example 1 and Comparative Example 1 were prepared. The appropriate amount of citric acid in Table 6 indicates the amount necessary to adjust the pH of the composition to 5.5, and the remaining amount of purified water is the amount necessary to make the total 100% by weight. Indicates.

100 g of the same Candida albicans test bacterial solution as in the experimental example was inoculated into 1 g of the composition of Example 1 and Comparative Example 1, and allowed to stand at 25 ° C. for 3 days. 100 μL of this diluted appropriately with purified water was smeared on a YM agar medium (Kanto Chemical Co., Inc.), and the number of colonies after culturing at 25 ° C. for 2 days was counted. The survival rate of Candida albicans was calculated by the following formula, and the results are shown in Table 6.
Survival rate (%) = (number of colonies in Example 1 / number of colonies in Comparative Example 1) × 100

  Compared with the composition of Comparative Example 1, the composition of Example 1 was able to significantly reduce the survival rate of Candida albicans.

  The other prescription example of this invention is shown.

Formulation Example 1: Skin composition (ointment)
Propylene glycol 5 (wt%)
Sodium benzoate 0.5
Bentonite 20
Kaolin 20
Glycerin 10
Sericin hydrolyzate 1
Methyl paraoxybenzoate 0.2
Purified water remaining (pH 6.3)

Formulation Example 2: Oral composition (gel agent)
Propylene glycol 5 (wt%)
Sodium benzoate 0.3
Glycerin 10
Xylitol 1
Sodium carboxymethylcellulose 5
Sericin hydrolyzate 1
Ethyl paraoxybenzoate 0.05
Purified water remaining (pH 5.5)

Formulation Example 3: Skin Composition (Lotion)
Propylene glycol 8 (wt%)
Sodium benzoate 0.05
Polyoxyethylene oleyl ether 1
Ethanol 5
Sericin hydrolyzate 1
Methyl paraoxybenzoate 0.2
Purified water remaining (pH 6.5)

Formulation Example 4: Scalp composition (aerosol)
Propylene glycol 5 (wt%)
Sodium benzoate 1
Isopropylmethylphenol 0.1
Ethanol 20
Sericin hydrolyzate 1
Purified water Remaining liquefied petroleum gas 50
(PH 6.5)

Claims (5)

  A composition for external use for suppressing the growth of Candida in skin and mucous membrane, comprising at least one selected from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate, and propylene glycol An external composition characterized by containing.   The total amount of sorbic acid and sorbate is 0.5% by weight or less, the amount of benzoic acid is 0.2% by weight or less, and the amount of benzoate is 1.0% in total. The total amount of at least one compound selected from the group consisting of sorbic acid, sorbate, benzoic acid, and benzoate is 0.01 to 1.5% by weight. The composition for external use according to claim 1, wherein the blending amount of propylene glycol is 0.5 to 15% by weight.   One or more selected from the group consisting of sorbic acid, sorbic acid salt, benzoic acid, and benzoic acid salt and propylene glycol are blended in a weight ratio of 1: 1 to 1: 200. The composition for external use according to claim 1 or 2.   The composition for external use according to any one of claims 1 to 3, comprising at least one selected from the group consisting of potassium sorbate and sodium benzoate and propylene glycol.   The external composition according to any one of claims 1 to 4, wherein the pH is 4.0 to 7.5.