Composition for mucosal washing

Abstract

To provide a composition for mucosal cleaning that has low stimulation and excellent antiseptic performance without using paraben.SOLUTION: A composition for mucosal cleaning contains (A) lactic acid and / or a salt thereof, and (B) sorbic acid and / or a salt thereof. Such a composition has low stimulation and excellent antiseptic performance without using paraben.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a mucosal cleansing composition having low irritation and excellent antiseptic properties.

Background Art

[0002] Paraben is a substance that exhibits excellent antibacterial and antiseptic abilities and is most widely used in compositions such as cosmetics and quasi-drugs (Patent Document 1). Specifically, as parabens, methylparaben, ethylparaben, propylparaben, butylparaben, etc. are used.

[0003] In mucous membranes such as the pharynx, nasal cavity, oral cavity, and vagina, it is known that discomfort due to dirt adhesion and inflammation and infections due to microorganism adhesion occur. In order to prevent and improve such symptoms in mucous membranes, it is considered effective to remove the adherents on the mucous membranes with a cleansing solution for mucous membranes. And also in such a cleansing solution for mucous membranes, parabens having high antibacterial and antiseptic performance are used (Patent Document 2).

[0004] On the other hand, parabens are also known to have problems such as irritation and allergy (Non-Patent Document 1). For this reason, it is desired to reduce the amount of parabens used or refrain from using them. However, since parabens themselves have excellent antibacterial and antiseptic abilities, it can still be said that it is difficult to substitute them for the purpose of minimizing the blending amount or eliminating the use of preservatives while ensuring the antibacterial and antiseptic properties of the composition itself.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present inventor is to provide a mucosal cleansing composition that has low irritation and excellent antiseptic properties without using parabens.

Means for Solving the Problems

[0008] As a result of intensive studies, the present inventor has found that in a composition for mucosal cleansing, by combining and blending lactic acid and / or its salts with sorbic acid and / or its salts, excellent antiseptic properties can be exhibited while having low irritation. The present invention has been completed by further studies based on this finding.

[0009] That is, the present invention provides an invention in the following aspects. Item 1. A mucosal cleansing composition containing (A) lactic acid and / or its salts, and (B) sorbic acid and / or its salts. Item 2. The mucosal cleansing composition according to Item 1, wherein the content of the component (A) is 0.5 to 2% by weight in total. Item 3. The mucosal cleansing composition according to Item 1 or 2, wherein the content of the component (B) is 0.005 to 0.5% by weight in total. Item 4. The mucosal cleansing composition according to any one of Items 1 to 3, having a pH of 3.8 to 8. Item 5. The mucosal cleansing composition according to any one of Items 1 to 4, used for vaginal mucosa.

Effects of the Invention

[0010] According to the mucosal cleansing composition of the present invention, excellent antiseptic properties can be exhibited while having low irritation.

Modes for Carrying Out the Invention

[0011] The composition for mucosal irrigation of the present invention is characterized by containing (A) lactic acid and / or its salt (hereinafter also referred to as the "(A) component"), and (B) sorbic acid and / or its salt (hereinafter also referred to as the "(B) component"). Hereinafter, the composition for mucosal irrigation of the present invention will be described in detail.

[0012] (A) Lactic acid and / or its salts The composition for mucosal irrigation of the present invention contains lactic acid and / or its salt as the (A) component.

[0013] Lactic acid (2-hydroxypropionic acid) and its salt are components that are formulated in cosmetics, quasi-drugs, etc. as a pH adjuster and / or a moisturizing component.

[0014] The salt of lactic acid is not particularly limited as long as it is a cosmetically or pharmaceutically acceptable salt. Specifically, examples of the salt of lactic acid include alkali metal salts of lactic acid (sodium lactate, potassium lactate, etc.), alkaline earth metal salts of lactic acid (calcium lactate, magnesium lactate, etc.), aluminum lactate, zinc lactate, silver lactate, copper lactate, iron lactate, manganese lactate, ammonium lactate, etc. These salts of lactic acid may be used alone or in combination of two or more. In the present invention, as the salt of lactic acid, preferably an alkali metal salt of lactic acid is mentioned, and more preferably sodium lactate is mentioned.

[0015] In the present invention, any of the L(+)-form, D(-)-form, and DL-form may be used as the (A) component. Specifically, as the (A) component, a DL-form obtained by a chemical synthesis method may be used, or an L(+)-form, D(-)-form, or DL-form obtained by a fermentation method using lactic acid bacteria may be used. In the present invention, among these (A) components, preferably the L-form is used.

[0016] Also, in the present invention, either lactic acid or the salt of lactic acid may be used as the (A) component, or both may be used in combination. In the present invention, as the (A) component, preferably lactic acid and the salt of lactic acid can be used in combination.

[0017] The content of component (A) in the composition for mucosal cleansing of the present invention is 0.5 to 2% by weight in total. From the viewpoint of obtaining more reduced irritation and / or more excellent preservative properties, the content of component (A) is preferably 0.7 to 1.5% by weight, more preferably 1 to 1.2% by weight in total. Further, when the component (A) contains lactic acid, the content of lactic acid is 0.1 to 1.8% by weight. From the viewpoint of obtaining more reduced irritation and / or more excellent preservative properties, when the component (A) contains lactic acid, the content of lactic acid is preferably 0.1 to 0.6% by weight, more preferably 0.2 to 0.4% by weight, still more preferably 0.3 to 0.36% by weight.

[0018] (B) Sorbic acid and / or its salts The composition for mucosal cleansing of the present invention contains sorbic acid and / or its salt as component (B).

[0019] The salt of sorbic acid is not particularly limited as long as it is a cosmetically or pharmaceutically acceptable salt. Specifically, examples of the salt of sorbic acid include alkali metal salts of sorbic acid (sodium sorbate, potassium sorbate, etc.), alkaline earth metal salts of sorbic acid (calcium sorbate, magnesium sorbate, etc.), ammonium salts of sorbic acid, and the like. These salts of sorbic acid may be used alone or in combination of two or more.

[0020] In the present invention, either one of sorbic acid and the salt of sorbic acid may be used as component (B), or both may be used in combination. In the present invention, sorbic acid can preferably be used as component (B).

[0021] The content of component (B) in the composition for mucosal irrigation of the present invention is 0.005 to 0.5% by weight in total. From the viewpoint of obtaining more reduced irritation and / or more excellent antiseptic properties, the content of component (B) is preferably 0.01 to 0.3% by weight, more preferably 0.04 to 0.2% by weight in total.

[0022] In the composition for mucosal irrigation of the present invention, the ratio of component (A) to component (B) is not particularly limited and is determined by the respective contents described above. From the viewpoint of obtaining more reduced irritation and / or more excellent antiseptic properties, the total content of component (B) relative to 1 part by weight of the total amount of component (A) is, for example, 0.005 to 0.5 part by weight. From the viewpoint of obtaining more reduced irritation and / or more excellent antiseptic properties, the total content of component (B) relative to 1 part by weight of the total amount of component (A) is preferably 0.01 to 0.3 part by weight, more preferably 0.03 to 0.2 part by weight.

[0023] Other components In the composition for mucosal irrigation of the present invention, in addition to the above components, other bases and additives required for formulation and the like may be included as long as the effects of the present invention are not impaired. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. Examples include aqueous bases such as water, lower alcohols having 1 to 5 carbon atoms, and polyhydric alcohols, surfactants, antiseptics, flavoring agents, coloring agents, thickeners, pH adjusters, wetting agents, stabilizers, antioxidants, ultraviolet absorbers, chelating agents, adhesives, buffers, solubilizing aids, solubilizers, preservatives, and other additives. These base materials and additives may be used alone or in combination of two or more. The content of these bases and additives can be appropriately set according to the dosage form and the like.

[0024] Among the above-mentioned bases and additives, the composition for mucosal irrigation of the present invention preferably contains water and polyhydric alcohol, and preferably includes water, propylene glycol and / or glycerin. When the composition for mucosal irrigation of the present invention contains polyhydric alcohol, the content of polyhydric alcohol is 8 to 20% by weight, preferably 10 to 18% by weight.

[0025] Among the above-mentioned bases and additives, the composition for mucosal irrigation of the present invention preferably does not substantially contain a preservative. "Not substantially containing a preservative" means that the concentration of the preservative is not included at a concentration that produces a preservative effect. Specifically, as the preservative, 0.01% by weight or less, preferably 0.001% by weight or less, more preferably 0.0001% by weight, and most preferably 0% by weight can be mentioned.

[0026] In addition to the above components, the composition for mucosal irrigation of the present invention may contain other pharmacological components as necessary within a range that does not impair the effects of the present invention. Examples of such pharmacological components include vitamins, antihistamines, local anesthetics, anti-inflammatory agents, skin protectants, blood circulation promoting components, cooling agents, mucopolysaccharides, and the like. These pharmacological components may be used alone or in combination of two or more. When these pharmacological components are contained, the content thereof may be appropriately set according to the type of pharmacological component used, the expected effect, and the like.

[0027] Form The pH (25°C) of the composition for mucosal irrigation of the present invention is not particularly limited as long as it does not damage the mucosa. For example, it is 3.8 to 8, preferably 3.9 to 6, more preferably 4 to 5, still more preferably 4 to 4.5, and even more preferably 4 to 4.3. From the viewpoint of exerting even better preservative properties against both Aspergillus brasiliensis and Candida albicans, the pH (25°C) of the composition for mucosal irrigation of the present invention is preferably 4 to 4.16. In order to adjust the composition of the present invention to such a pH, it can be carried out according to a conventionally known method. For example, hydrochloric acid, acetic acid, citric acid, gluconic acid, succinic acid, tartaric acid, maleic acid, sulfuric acid, phosphoric acid, malic acid, arginine, aqueous ammonia, diisopropanolamine, diethanolamine, triisopropanolamine, triethanolamine, monoethanolamine, potassium hydroxide, calcium hydroxide, sodium hydroxide, and buffers such as salts thereof can be appropriately added. Further, the pH can also be adjusted by adjusting the amount of lactic acid and / or its salt in component (A).

[0028] The dosage form of the composition for mucosal irrigation of the present invention is not particularly limited. For example, forms such as solutions, pastes, ointments, powders, granules, tablets, and creams can be mentioned. Among these, a preferred example of the dosage form of the composition for mucosal irrigation of the present invention is a solution.

[0029] Further, the composition for mucosal irrigation of the present invention may be provided as a product containing each component at the above-mentioned concentration, or may be provided as a concentrate that is prepared by appropriately diluting with water or the like at the time of use so that the concentration of each component becomes the above-mentioned concentration.

[0030] Use The composition for mucosal cleansing of the present invention has low irritation to the mucosa and excellent preservative properties, and thus is used for mucosal cleansing. The mucosa to which the composition for mucosal cleansing of the present invention is applied is not particularly limited, and for example, it can be applied to the mucosa of the nasal cavity, pharynx, oral cavity, ear, vagina, bladder, rectum, etc., and preferably can be applied to the mucosa of the vagina. In particular, when the composition for mucosal cleansing of the present invention is applied to the vagina, the composition for mucosal cleansing of the present invention exhibits antibacterial properties against bacteria associated with bacterial vaginitis (BV) and does not exhibit antibacterial properties against Lactobacillus, which is a resident bacterium in the vagina, and can be used for the purpose of selective antibacterial.

[0031] The method of using the composition for mucosal cleansing of the present invention is not particularly limited as long as a cleansing effect is achieved. For example, a method of dropping it on the mucosa, a method of spraying it on the mucosa with a spray or the like, a method of injecting it with a catheter or the like, in the case of the nasal cavity, a method of pouring the cleansing liquid into the nasal cavity and spitting it out from the mouth, or a method of pouring the cleansing liquid into one nasal cavity and spitting it out from the other nasal cavity, in the case of the oral cavity, a method of gargling by holding it in the mouth and a method of polishing with a brush, in the case of the vagina, a method of injecting it into the vaginal cavity and allowing it to flow out from the vaginal orifice, etc. can be mentioned.

[0032] In addition, the applicable amount of the composition for mucosal cleansing of the present invention during cleansing is not particularly limited and can be appropriately set in consideration of the size of the application site, the degree of foreign matter adhesion to the mucosa, etc. For example, in the case of aiming at cleansing the nasal mucosa, it is 10 to 30 mL, preferably 15 to 25 mL, in the case of aiming at cleansing the ear mucosa, it is 0.2 to 1 mL, preferably 0.2 to 0.7 mL, in the case of aiming at cleansing the oral mucosa, it is 5 to 30 mL, preferably 10 to 20 mL, and in the case of aiming at cleansing the vaginal mucosa, it is 50 to 200 mL, preferably 100 to 140 mL.

Examples

[0033] Examples are shown below to more specifically explain the present invention, but the present invention is not limited thereto.

[0034] Test examples Compositions for mucosal irrigation having the compositions shown in Tables 1 and 2 were prepared. The details of component (A) shown in Table 1 are as follows. The compositions for mucosal irrigation shown in Table 1 were in liquid form. · Lactic acid (fermented product containing 90 wt% lactic acid; trade name Musashino Lactic Acid 90F; manufactured by Musashino Chemical Laboratory, Ltd.). The numerical values in the table indicate the amount of lactic acid contained in the lactic acid material. · Sodium lactate (fermented product containing 50 wt% sodium lactate; trade name Sodium Lactate F; manufactured by Musashino Chemical Laboratory, Ltd.). The numerical values in the table indicate the amount of sodium lactate contained in the sodium lactate material. Also, in all the compositions for mucosal irrigation, the total amount of lactate ions and lactic acid molecules in the composition was adjusted to 1.0 wt%.

[0035] <Antiseptic Efficacy Test> The antiseptic efficacy test was carried out by the Asaka method shown below. (1) Aspergillus brasiliensis (KPB1042) was spread on SCD medium and Candida albicans (KPB1039) was spread on PDA medium with a platinum loop and pre-cultured at 35 °C for 18 - 24 hours. (2) The pre-cultured bacteria were collected with a 10 μL plastic platinum loop to fill a mortar and suspended in 10 mL of physiological saline to prepare an A. brasiliensis spore solution and a C. albicans bacterial solution. (3) 0.1 mL of the spore solution or bacterial solution was inoculated into the composition for mucosal irrigation that had been pre-aliquoted at 20 g, stirred, and the initial bacterial count was measured. (4) It was stored at 25 °C, and the bacterial counts after 1 week (1w), 2 weeks (2w), and 4 weeks (4w) were measured. The measured bacterial counts were expressed as relative values (%) with the initial bacterial count as 100%. The results are shown in Tables 1 and 2.

[0036] <Bactericidal Efficacy Test> As test bacteria, the following bacteria associated with bacterial vaginitis (BV) and Lactobacillus (commensal bacteria in the vagina) were used, and the selective bactericidal ability was tested assuming the case of applying the composition for mucosal irrigation to the vaginal mucosa. The details of the bacterial species, growth medium, and agar medium for viable bacteria count measurement of each bacterium are as follows.

[0037] · BV bacterium - 1 Test bacterial strain: Fusobacterium nucleatum subsp. Nucleatum ATCC 25586 Growth medium: F. nucleatum → Modified GAM liquid medium Agar medium for viable cell count: Modified GAM agar medium supplemented with fetal bovine serum at a final concentration of 10% by weight

[0038] · BV bacterium - 2 Test bacterial strain: Mobiluncus curtisii ATCC 35241 Growth medium: Modified GAM liquid medium supplemented with fetal bovine serum at a final concentration of 10% by weight Agar medium for viable cell count: Modified GAM agar medium supplemented with fetal bovine serum at a final concentration of 10% by weight

[0039] · Lactobacillus Test bacterial strain: Lactobacillus crispatus ATCC 33820 Growth medium: MRS liquid medium supplemented with fetal bovine serum at a final concentration of 10% by weight Agar medium for viable cell count: MRS agar medium

[0040] The above three test bacterial strains were subjected to a 24 - hour test at 37°C in an environment of 93% by volume of nitrogen, 5% by volume of carbon dioxide, and 2% by volume of oxygen. Specifically, the following procedures were carried out.

[0041] (1) Preparation of test bacterial solution 1. The preserved bacterial strain was transplanted onto MRS agar medium and pre - cultured anaerobically using AnaeroPack - Kenki at 37°C for 24 hours. 2. After pre - culture, the test bacterial strain was prepared using a three - fold concentrated growth medium to a concentration of approximately 1.0×10 7 CFU / ml / L as the test bacterial solution.

[0042] (2) Adjustment of the action environment 1. A container filled with a predetermined amount of liquid nitrogen was placed inside the glove box. Also, a sealed container used for the action of the test sample and the test bacterial solution was placed inside the glove box with the lid open. 2. It was left standing for a predetermined time to vaporize the liquid nitrogen and replace the air inside the glove box with nitrogen. 3. Using the air in the laboratory, the oxygen concentration inside the glove box was adjusted to 2%. 4. Using the experimental gas (carbon dioxide), the carbon dioxide concentration inside the glove box was adjusted to 5%.

[0043] (3) 1. Inside the safety cabinet, the test sample (composition for mucosal washing) and the test bacterial solution were mixed at a ratio of 2:1 and dispensed into petri dishes. 2. The petri dishes dispensed inside the glove box adjusted in (2) were placed into the pre - installed sealed container, and the petri dishes were placed inside the glove box and sealed with the lid. 3. The sealed container with the lid was taken out of the glove box and allowed to act at 37°C for a predetermined time. 4. Inside the safety cabinet, 0.5 mL of the test bacterial suspension after standing for a predetermined time was added to 4.5 mL of SCDLP and mixed. 5. Using AnaeroPack - Kenki, the viable cell count was measured by the pour plate culture method. The results are shown in Table 2.

[0044] <Irritation Evaluation Test> (1) Preparation of the cultured corneal model LabCyte CORNE - MODEL24 The assay medium was warmed and 0.5 mL was added to each well in the first row of a 24 - well assay plate. The cultured corneal model LabCyte CORNEA - MODEL24 (lot number LCC24 - 191014 - A) was transferred to the first row of the 24 - well assay plate. The 24 - well assay plate was placed in a CO2 incubator and left standing overnight.

[0045] (2) Application and washing of the test substance The PBS was warmed and 0.5 mL of it was added to each well in the third row of a 24-well assay plate. The test substance (the composition for mucosal washing) was placed in an amount of 50 μL on the cultured epidermis in the culture cup and spread evenly over the whole. After exposure for 7 minutes, the cultured corneal model was washed 20 times, the moisture was wiped off with a sterilized cotton swab, and it was transferred to the third row of the 24-well assay plate.

[0046] In the above (1) and (2), exposure and washing were carried out for each one plate (using 6 wells). The test in (3) described below was carried out for each two plates (a total of 12 wells). In (1) to (3), the samples and the PBS for washing were used after warming to 37°C. The work was carried out on a hot plate at 32°C.

[0047] (3) WST-8 Test The EBSS was warmed at 37°C and diluted so that the volume ratio of Cell Counting Kit-8:EBSS was 1:10 to prepare a WST-8 dilution solution, and 0.3 mL of it was added to each well in the fourth row of a 24-well assay plate. The moisture on the cultured corneal model was wiped off with a sterilized cotton swab and transferred to the fourth row of the 24-well assay plate. For the blank, the WST-8-added medium was placed in an empty well. The plate was placed in a CO2 incubator and reacted for 3.5 hours. After the reaction was completed, the culture cup was taken out, and 200 μL of the WST-8 reaction solution was transferred to a 96-well plate. In addition, 200 μL of the blank medium was placed in A1. The absorbance at 450 nm and 650 nm was measured with a microplate reader.

[0048] (4) Calculation of the survival rate of human corneal cells The value obtained by subtracting the absorbance at 650 nm from the absorbance at 450 nm was taken as the measured value, and the viability rate of the test substance was calculated based on the following formula. The results are shown in Table 2.

[0049]

Equation

[0050]

Table 1

[0051]

Table 2

[0052] As shown in Table 1 and Table 2, the mucosal cleansing compositions (Examples 1 to 4) containing lactic acid, sodium lactate, and sorbic acid had low irritation and excellent preservative properties. On the other hand, the mucosal cleansing composition (Comparative Example 2) containing glycine known as a preservative had high irritation and poor preservative properties. Furthermore, as shown in Table 2, the mucosal cleansing composition (Example 4) containing lactic acid, sodium lactate, and sorbic acid showed antibacterial activity against bacteria associated with bacterial vaginitis (BV) when applied to the vaginal mucosa, and did not show antibacterial activity against Lactobacillus, which is a resident bacterium in the vagina, and also had selective antibacterial properties.

[0053] Formulation examples Liquid mucosal cleansing compositions with the formulations shown in Table 3 were prepared. The lactic acid materials and sodium lactate materials used in each mucosal cleansing composition were the same as in the test examples, and the numerical values in the table indicate the amount of lactic acid contained in the lactic acid material and the amount of sodium lactate contained in the lactic acid material. All of the mucosal cleansing compositions had low irritation and excellent preservative properties, and also had selective antibacterial properties against bacteria associated with bacterial vaginitis (BV) when applied to the vaginal mucosa.

[0054]

Table 3

Claims

Claim 1: A mucosal cleansing composition (excluding those containing hyaluronic acid esterified with benzyl alcohol) that contains (A) lactic acid, an alkali metal lactate, an alkaline earth metal lactate, aluminum lactate, silver lactate, copper lactate, iron lactate, manganese lactate, and / or ammonium lactate, and (B) sorbic acid and / or a salt thereof, has a pH of 3.8 to 6, is used for vaginal mucosa, and is used for selective antibacterial action that exhibits antibacterial activity against Mobiluncus curtisii and does not exhibit antibacterial activity against Lactobacillus crispatus.

2. The mucosal cleansing composition according to claim 1, wherein the content of the component (A) is 0.5 to 2% by weight in total.

3. The mucosal cleansing composition according to claim 1 or 2, wherein the content of the component (B) is 0.005 to 0.5% by weight in total.

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