JP2005139075A - Agent for controlling balance of ecosystem of indigenous bacterium in skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an agent for controlling balance of ecosystem of indigenous bacteria in the skin, not exhibiting sterilizing action on Staphylococcus epidermidis which is a useful bacterium and having sterilizing action or proliferation-suppressing action on Staphylococcus aureus which is a harmful bacterium. <P>SOLUTION: This agent for controlling balance of ecosystem of indigenous bacteria in the skin comprises bittern as an active ingredient. The effect of the agent is synergistically improved by combinedly using the agent with one or more kinds of plant extracts selected from rosemary extracts and Glycyrrhizae Radix extracts. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention provides an ecological balance adjusting agent for skin resident bacteria, that is, it does not exhibit bactericidal action against Staphylococcus epidermidis , which is a beneficial bacterium, and is a toxic bacterium, Staphylococcus aureus. On the other hand, the present invention relates to an ecosystem balance adjusting agent for skin resident bacteria having a bactericidal or growth-inhibiting action.

  Healthy skin is protected by an ecosystem of beneficial resident bacteria. The effects of these beneficial bacteria are as follows. (1) Protect moisturizing ingredients and prevent dry skin. (2) It has an ultraviolet absorption effect and protects the skin from harmful ultraviolet rays. (3) Decompose active oxygen and prevent aging. (4) Prevent invasion of harmful bacteria and prevent inflammation. (5) Shows fibroblast proliferation action and prevents wrinkles. (6) Adjust the pH of the epidermis and increase the resistance.

  However, if beneficial bacteria are reduced or killed for some reason, or if the balance is lost and the proportion of harmful bacteria increases, the above-mentioned effects are not exhibited, and skin diseases may be caused. Therefore, antibacterial agents and bactericides have been applied to the skin for the purpose of removing such harmful bacteria.

Staphylococcus aureus, in particular, is a Gram-positive bacterium that causes vomiting-related food poisoning and various abscesses. The enterotoxin produced by this method causes food poisoning, and as a superantigen like enterotoxin B and toxic shock syndrome toxin-1 (TSST-1), exacerbation of atopic dermatitis Those related to allergic diseases are known. Enterotoxin B has a property of directly binding to a class II molecule of a major histocompatibility complex on an antigen presenting cell and a Vβ region of a T cell receptor as a superantigen without being processed by the antigen presenting cell. It is believed that the T cell group expressing a specific Vβ that binds to the superantigen is activated at once to promote the production of a large amount of cytokines and to have a significant effect on the immune response of the living body. Enterotoxin B and TSST-1, which are superantigens of S. aureus, stimulate skin Langerhans cells and macrophages to produce interleukin-1, tumor necrosis factor, and interleukin-12. Induces the expression of skin lymphocyte-binding antigen (CLA), a skin homing receptor, in activated T cells.

  As mentioned above, as enterotoxin produced by Staphylococcus aureus is found to be involved in allergic diseases in addition to food poisoning, active screening of drugs with antibacterial or bactericidal activity against Staphylococcus aureus has been actively conducted. I have been. As such drugs, recently, Mannentake fruit body umbrella extract (see Patent Document 1), antibacterial spices such as clove, allspice, oregano (see Patent Document 2), Kudin extract (see Patent Document 3), Jackfruit Extract (see Patent Literature 4), altocarpine and sophoraflavanone G (see Patent Literature 5), xanthone derivative (see Patent Literature 6), birch extract (see Patent Literature 7), chitosan derivative (see Patent Literature 8), Fine particle titanium oxide having photocatalytic activity (see Patent Document 9), stevia extract (see Patent Document 10), alkenyl isothiocyanate compound (see Patent Document 11), hop, forsythia, syringen, chrysanthemum, tokinsenka, calendula , Honeysuckle, Warbler, Salvia and its variants None and genus plant, striped bamboo, nettle, Miyama Nettle causes, such as one or more plant extracts selected from Kurobanahikiokoshi (see Patent Document 12) are disclosed.

  Also known are detergents containing N-acylglutamate for the removal of Staphylococcus aureus (see Patent Document 13) and bacterial enterotoxin neutralizers containing iron-bound lactoferrin (see Patent Document 14). It has been.

However, most of the techniques described above are intended to bacteriostatically or kill or eliminate Staphylococcus aureus. Staphylococcus epidermidis , Bacteroides spp., Eubacterium spp., Streptococcus ) Genus, bifidobacteria (genus Bifidobacterium genus) resident bacteria in the skin and intestines, bacteriostatic, bactericidal action, or remove these, resulting in changes in the resident flora, skin and intestines May affect the homeostasis of the child and may cause an opportunistic infection. Moreover, since the enterotoxin neutralizer which has a lactoferrin as a main component is a protein formulation, there are many restrictions in obtaining a stable formulation, and expression of sensitization is also feared.

  Therefore, screening for substances that selectively inhibit the growth of Staphylococcus aureus, which is attracting attention as a disease-causing fungus, is being conducted rather than the growth of Staphylococcus epidermidis, a representative bacterium of the normal flora of healthy skin. Antibacterial compositions obtained from, for example, skin-derived bacteria, Propionibacterium granulosum (see Patent Document 15), buttonpi, licorice, oolong tea, rosemary, clara, oren, psyllium, thyme, aloe, peanut A selective antibacterial composition characterized in that it contains one or more plant extract selected from mongoose, cordyceps, sensou, tsugashiwa, lyobu, enraiso, capsicum (see Patent Document 16), etc. ing. However, these are components derived from natural products, and there are problems such as large variations in quality and difficulty in commercialization, and a large amount of application required to obtain an effective amount.

  In addition, bittern is a liquid obtained by crystallization of salt from seawater or a dried product thereof. The composition of bittern varies depending on the salt production method (ion exchange membrane method, solar method, salt field method or evaporation method), temperature at the time of salt crystallization, salt concentration and pressure at the time of salt crystallization, and other conditions. Table 1 shows an example of the composition of bittern with different salt production methods (see Non-Patent Document 1). In addition, the unit of the numerical value of Table 1 is g / 100g. In addition, regarding the bittern by the ion exchange membrane method, it varies depending on the characteristics of the ion exchange membrane.

  In addition, attempts to blend bittern into an external preparation for skin have been made for a long time, and recently, a hair nourishing agent containing bittern as an active ingredient (see Patent Document 17), a makeup containing magnesium ions and calcium ions in a specific ratio. Inventions relating to specific effects such as skin protection ability and barrier function recovery effect (see Patent Document 18), skin moisturizing and protective agents used in combination with urea, glycerin and alum (see Patent Document 19), fish skin elastin and The skin external preparation (refer patent document 20) excellent in the moisturizing and skin protection effect used together (refer patent document 20), the composition (refer patent document 21) etc. which have the skin state improvement effect | action combined with phytoncide and chitosan are disclosed.

JP-A-6-116162 JP-A-7-267873 JP-A-8-73364 JP-A-8-73368 JP-A-8-73372 Japanese Patent Laid-Open No. 9-110688 JP-A-10-120589 JP 10-158305 A Japanese Patent Laid-Open No. 11-5729 Japanese Patent Laid-Open No. 11-43443 Japanese Patent Laid-Open No. 11-137949 JP 2001-226280 A Japanese Patent Laid-Open No. 11-80781 Japanese Patent Laid-Open No. 11-279076 Japanese Patent Laid-Open No. 9-20638 JP 2001-226213 A Japanese Patent Laid-Open No. 11-1414 JP 2002-47119 A JP 2000-109421 A JP 2001-39826 A JP 2001-131018 A "Inorganic Industry Overview", Baifukan Co., Ltd., 1995, p. 38-39

  The object of the present invention is to distinguish Staphylococcus epidermidis resident in healthy skin from harmful Staphylococcus aureus always present in skin with skin disease, without affecting the growth of resident Staphylococcus epidermidis resident. To provide an ecosystem balance regulator for skin resident bacteria that exerts sufficient effects on the treatment and prevention of knee diseases such as atopic dermatitis by having antibacterial action only on harmful Staphylococcus aureus is there.

The harmful bacterium Staphylococcus aureus and the beneficial bacterium Staphylococcus epidermidis mentioned in the present invention are fairly similar in taxonomy, and are generally distinguished by sterilization or growth. It is extremely difficult to suppress. However, as a result of intensive studies, the present inventor has negatively affected the growth of beneficial Staphylococcus epidermidis by inhibiting only the growth of harmful Staphylococcus aureus from over 2000 active ingredients for external use. It has been found that there is no such thing, and the present invention has been completed.

  That is, the ecosystem balance adjusting agent for skin resident bacteria in the present invention is characterized by blending bittern as an active ingredient. Moreover, in the ecological balance regulator of the skin resident bacteria of the present invention, the effect is synergistic by further using one or two kinds of plant extracts selected from rosemary extract and licorice extract. Improve.

  The ecological balance adjusting agent for skin resident bacteria of the present invention distinguishes Staphylococcus epidermidis resident in healthy skin and Staphylococcus aureus present in skin with skin diseases, and for the growth of beneficial staphylococcus epidermidis Has no effect and has antibacterial effect only on harmful Staphylococcus aureus. Moreover, the ecosystem balance regulator of the skin resident bacteria of this invention has the said selective antibacterial effect, and can exhibit sufficient effect for treatment and prevention of skin diseases, such as atopic dermatitis.

  The bittern used in the present invention is a solution obtained by crystallization of salt from seawater, a dried product thereof, or an artificially mixed mineral. The composition of bittern varies depending on the production area, salt production method (ion exchange membrane method, sun method, salt field method or evaporation method), temperature at the time of salt crystallization, salt concentration and pressure at the time of salt crystallization, and other conditions. However, bittern prepared from seawater collected in the sea area around the Tokara Islands or in the sea area around Minami Daito Island is free of contaminants such as organic phosphate compounds contained in the seawater, and is highly effective.

  In the present invention, the rosemary extract and licorice extract used in combination with bittern are described.

Rosemary (Rosmarinus officinalis L.) is an evergreen shrub belonging to the Labiatae (Labiatae), leaves, branches, bark, it is possible to use the site and the entire tree of flowers, etc., it is preferable to use a leaf. Licorice (Glycyrrhiza uralensis Fisher, Glycyrrhiza glabra L. , Glycyrrhiza echinata L., Glycyrrhiza glandulifera Reg. Et Herd., Glycyrrhiza glabra var. Typica Regel et Herder, Glycyrrhiza glabra var. Violacea Boiss., Glycyrrhiza glabra var. Pallida Boiss) is, It is a perennial plant belonging to the leguminosae family ( Leguminosae ) and is the base plant of the herbal medicine " Glycyrrhizae Radix ". For extraction, each part such as leaves, stems, flowers, roots, and whole plants can be used, but roots are preferably used.

  In the present invention, in order to obtain a rosemary extract or licorice extract, each plant may be subjected to extraction as it is. However, in consideration of extraction efficiency, after performing processing such as shredding, drying, and grinding. Extraction is preferably performed. Extraction is performed by immersing in an extraction solvent. In order to increase the extraction efficiency, stirring may be performed or homogenization may be performed in an extraction solvent. The extraction temperature is suitably about 5 ° C. to the boiling point of the extraction solvent. The extraction time varies depending on the type of extraction solvent and the extraction temperature, but is suitably about 4 hours to 14 days.

  Extraction solvents include water, lower alcohols such as methanol, ethanol, propanol, and isopropanol, polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, dipropylene glycol, and glycerin, and ethers such as ethyl ether and propyl ether. , Polar organic solvents such as esters such as ethyl acetate and butyl acetate, and ketones such as acetone and ethyl methyl ketone can be used, and one or more of these are selected and used. Further, physiological saline, phosphate buffer, phosphate buffered saline, or the like may be used.

  In the present invention, the extract of rosemary or licorice by the above solvent can be contained in the external preparation for skin according to the present invention as it is, but the concentrated and dried solid can be dissolved again in water or a polar solvent, Alternatively, it may be used after performing purification treatment such as decolorization, deodorization, desalting, etc. within the range not impairing the skin physiological function improving action, or after fractionation treatment by column chromatography. For storage, it can be freeze-dried after purification and dissolved in a solvent before use. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.

  In the present invention, the mixing ratio in the case of using one or two extracts selected from bittern, rosemary extract and licorice extract is not particularly limited, and is suitably in the range of about 1: 100 to 100: 1. can do.

  The ecosystem balance regulator of skin resident bacteria in the present invention can be applied to the skin as it is. If necessary, starch, lactose, microcrystalline cellulose, excipients such as magnesium aluminate metasilicate, lubricants such as magnesium stearate and talc, binders such as gelatin, shellac, polyvinylpyrrolidone, methylcellulose, hydroxyethylcellulose, etc. , Disintegrating agents such as carboxymethylcellulose calcium, moisturizers such as sorbitol and glycerin, antioxidants such as dibutylhydroxytoluene, butylhydroxyanisole and tocopherol, absorption promoters, surfactants, tonicity agents and the like by known methods As an oral preparation such as soft capsule, hard capsule, tablet, pill, granule, powder, suspension, liquid, syrup, emulsion, elixir, injection, suppository, pessary or external preparation Can be provided.

  Since the ecological balance regulator for skin resident bacteria according to the present invention is hypoallergenic and does not exhibit toxicity or sensitization, it is particularly suitable for oral administration or topical application on the skin. It is useful as an oral preparation or food additive for preventing or alleviating symptoms of allergic diseases involving superantigens such as exacerbation of atopic dermatitis and preventing food poisoning, and also has excellent stability. It is.

[Example 1] Tokara Nigari Brine was prepared from seawater collected in the sea area around the Tokara Islands using a polyamide composite reverse osmosis membrane. The resulting brine was heated at 110 ° C. to separate it into bittern and salt, thereby obtaining Tokaranigari.

[Example 2] Minami Daito Island Nigali Brine was prepared from seawater collected in the sea area around Minami Daito Island using a polyamide composite reverse osmosis membrane. The obtained brine was heated at 113 ° C. and separated into bittern and salt to obtain bitter gourd Minamidaitojima bittern.

[Example 3] Nigali Dover Strait Brine was prepared from seawater collected in the sea area around the Dover Strait using a polyamide composite reverse osmosis membrane. The resulting brine was heated at 112 ° C. and separated into bittern and salt to obtain bitter gourd bittern.

[Example 4] Synthetic bittern sodium chloride (reagent special grade) 5.0 g, potassium chloride (reagent special grade) 3.0 g, magnesium chloride hexahydrate (reagent special grade) 15.0 g, calcium chloride (reagent special grade) 5.0 g Were mixed to obtain a synthetic bittern.

  About said Example 1- Example 4, the antimicrobial effect with respect to Staphylococcus epidermidis and Staphylococcus aureus was evaluated. The evaluation was performed using 1 mL of a sample solution diluted with water, 0.5 mL of Staphylococcus epidermidis dispersion, and 0. Mix mL and incubate at 37 ° C for 7 hours. After transplanting to a nutrient medium and culturing at 37 ° C. for 48 hours, the number of viable bacteria was counted. A similar evaluation was made by substituting purified water for the bittern solution and used as a control. The results are shown in Table 2 as relative values when the number of inoculated bacteria is 1.

  As shown in Table 2, the bittern of the present invention did not show a bactericidal effect against Staphylococcus epidermidis, which is a beneficial bacterium, and the number of viable bacteria in the inoculated state tended to be maintained or slightly increased. On the other hand, it showed a bactericidal action against Staphylococcus aureus, and the number of viable bacteria decreased from the number of inoculated bacteria. On the other hand, in the control, the number of viable bacteria was significantly increased in both Staphylococcus epidermidis and Staphylococcus aureus.

  Next, another embodiment of the present invention will be described.

  Gel agents according to Examples 5 to 7 of the present invention were prepared according to the formulations shown in Table 3. The lotion was prepared by mixing, dissolving and homogenizing all ingredients.

[Example 8] Oral solution A 200 ml of a simple syrup was added to 150 mg of Example 1, and then purified water was added to 1.0 L to obtain an internal solution.

  Clinical trials were conducted on Examples 5 to 8 of the present invention. A group of 20 patients with atopic dermatitis presenting with skin symptoms such as pruritus and skin eruption. Each group was blinded with Examples and Comparative Examples, and Examples 5 and 7 were twice daily. It was applied to the affected area for 3 days, and Example 8 was taken 3 times a day for 3 days to evaluate pruritus and improvement of skin symptoms. As a comparative example, in Example 5 and Example 8, what replaced the bittern, rosemary extract and licorice extract according to the present invention with a chlorhexidine gluconate solution was used in Comparative Example 1 and Example 8, and A comparative example 2 was obtained by substituting the bittern with a glucose solution. The improvement status of pruritus and skin symptom was evaluated in 4 stages of “Improved”, “Slightly improved”, “No change” and “Deteriorated”, respectively, compared with the state before starting use, and each evaluation was obtained The panel number is shown in Table 3.

  In addition, in the above clinical trials, the flora of the skin and intestines were investigated, and the extent of the change was “○: Almost no change”, “△: Some change”, “×: Significant change” Is also shown in Table 4.

  As is clear from Table 4, in the groups used in Examples 5 to 7 of the present invention, there were no panelists that showed pruritus and deterioration of skin symptoms in all groups, and an improvement tendency of these symptoms was also observed. It was. Moreover, no change was observed in the skin flora. Furthermore, in the group taking Example 8 which is an oral preparation, there were no panelists who showed pruritus and deterioration of skin symptoms, and both the pruritus and skin symptoms showed an improvement trend in 65% or more of panelists in both groups. It was. No changes in intestinal flora were observed.

  On the other hand, in the use group of Comparative Example 1, a considerable number of panelists showing a tendency to improve pruritus and skin symptoms were observed, but there were a few panelists whose symptoms worsened. Furthermore, the change of skin flora was recognized remarkably. Further, in the group taking Comparative Example 2, although no change in the skin bacterial flora was observed, the tendency to improve pruritus and skin symptoms was hardly observed, and the deterioration of symptoms was recognized in 60% or more panelists.

  In addition, about the said Example 5-Example 7, skin primary irritation and skin sensitization were not recognized at all, and oral toxicity, sensitization, and teratogenicity were not recognized also about Example 8. In Examples 1 to 8 of the present invention, even when stored at 25 ° C. for 6 months, no change in the state of the preparation was observed, and no decrease in antibacterial activity was observed.

Claims (2)

An ecological balance adjuster for skin resident bacteria containing bittern as an active ingredient. The ecological system balance regulator of the skin resident bacteria of Claim 1 which used together the 1 type or 2 types of plant extract selected from a rosemary extract and a licorice extract.