JP2700070B2 - Antimicrobial agent for Gram-positive anaerobic bacteria, external preparation for skin and oral composition using the same - Google Patents

Description

The present invention relates to an antibacterial agent for gram-positive anaerobic bacteria, an external preparation for skin and an oral composition using the same, and particularly to an improvement in an antibacterial active ingredient thereof.

[Prior art] Many antibacterial agents contained in plants are known and have high safety to the human body.
It is expected to be applied to cosmetics.

As such a plant antibacterial agent, particularly, piciferic acid extracted from a plant belonging to the cypress family or ferruginol, which is an analog thereof, is well known (for example, Hi
Roshi Fukui et al. Agric. Biol. Chem., 42 (7), 1419-1423,
1978, JP-A-62-56422).

[Problems to be Solved by the Invention] Problems of the Prior Art However, as for the antibacterial activity of the above-mentioned ferruginol, there are only reports on those belonging to Gram-negative enterobacteria, Gram-positive Staphylococcus aureus and Bacillus subtilis. , Gram-positive anaerobic bacteria that have completely different properties from those reported above, such as Streptococcus mutans (Stre
ptococcus mutans, acne (acne vulgaris: Acne vulg)
There has been no report on Propionibacterium acnes, which is the causative agent of Aris).

Object of the Invention The present invention has been made in view of the above-mentioned problems of the prior art, and its object is to provide antibacterial agents having a broad antibacterial action against Gram-positive anaerobic bacteria and bacteria causing periodontal diseases such as dental caries. An object of the present invention is to provide an effective oral composition and an external preparation for skin which is effective against bacteria causing skin diseases such as acne vulgaris.

In order to achieve the above object, the present inventors have conducted intensive research on substances having various antibacterial activities, and as a result, ferruginol has a strong antibacterial property against gram-positive anaerobic bacteria including bacteria causing periodontal disease or acne vulgaris. The present inventors have found that the substance has an action, and have completed the present invention.

[Means for Solving the Problems] That is, the invention according to claim 1 is an antibacterial agent for Gram-positive anaerobic bacteria, which comprises ferruginol.

The invention according to claim 2 is an external preparation for skin, characterized by containing ferdinol.

A third aspect of the present invention is an oral composition comprising ferruginol.

 Hereinafter, the configuration of the present invention will be described in detail.

Antimicrobial Agent for Gram-Positive Anaerobic Bacteria Containing Ferdinol Compound Ferruginol (4b, 5,6,7,8,8
a, 9,10-Octahydro-2-isopropyl-4b, 8,8-trimethyl- (4bS-trans) -3-phenanthrenol) has the following structure.

This ferdinol is a natural product contained in plants of the family Oysteraceae and Cypress, but can also be synthesized.

Ferruginol of the present invention is a Streptococcus mutans (Streptococcus mutans) which is a gram-positive anaerobic bacterium and is a causative bacterium of periodontal diseases such as tooth decay as shown in the test examples described below.
occus mutans) and Propionibacterium acnes, the causative agent of acne
Shows excellent antibacterial activity against

The antimicrobial agent for gram-positive anaerobic bacteria of the present invention is orally or parenterally administered, the dosage is determined by the patient's age, health condition, body weight, etc., but generally the daily dose of ferdinol is 0.5 to 50 mg / Kg body weight.

For oral administration, they are used in the form of tablets, capsules, powders, liquids and the like, and for parenteral administration, they are used in liquid or solid form.

Skin external preparation containing ferdinol The skin external preparation containing ferdinol can be used for any purpose, and is widely used in pharmaceuticals, quasi-drugs, cosmetics, and tray products. For example, lotions, emulsions, creams,
Packs, aqueous ointments, oily ointments, deodorants and the like.

In addition, in the skin external preparation of the present invention, in addition to ferruginol, a surfactant, a humectant, a lower alcohol, a thickener, an oil, an ultraviolet absorber, a fragrance, an antioxidant, a chelate according to the dosage form, if necessary. Ingredients commonly used in external preparations for skin, such as agents, pigments, preservatives, and fungicides, can be added.

Oral composition containing ferdinol The use of the oral composition containing ferdinol is also arbitrary, and examples thereof include dentifrices, mouthwashes, and deodorants.

The oral composition of the present invention may contain various components commonly used in oral compositions in addition to the ferruginol.

For example, dibasic calcium phosphate, abrasives such as silica,
Wetting agents such as glycerin and sorbitol, thickeners such as carboxymethylcellulose, surfactants, oils, lower alcohols, fragrances, pigments, preservatives and fungicides, and other anti-caractants do not impair the effects of the present invention. It can be blended in the range.

In the present invention, the amount of ferruginol added to the external preparation for skin or the composition for oral cavity is preferably 0.001 to 10% by weight, more preferably 0.01 to 1.0% by weight.

If it is less than 0.0001%, the antibacterial property is poor, and if it exceeds 10% by weight, it is disadvantageous in terms of cost.

Further, the dosage form of the external preparation for the skin and the composition for the oral cavity of the present invention is arbitrary, and may be a solid system, a solution system, a solubilizing system, an emulsion system, a powder dispersion system, a water-oil two-layer system, a water-oil-powder. Any dosage form such as a three-layer system may be used.

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

The present invention is not limited by this. Further, the compounding amount is shown by weight%.

Antibacterial agent First, examples of the antibacterial agent for gram-positive anaerobic bacteria according to the present invention and the antibacterial effect thereof will be described.

Example 1 Inhibitory Effect on Gram-Positive Anaerobic Bacteria First, the growth inhibitory effect on Gram-positive anaerobic bacteria Acne was examined as follows.

Using Nissui GAM agar medium as the medium, the pH was 7.3 ± 0.1.
After the adjustment, the minimum inhibitory concentration (MIC) of ferdinol with respect to the Propionibacterium acnes standard strain (ATCC 11827) was measured and evaluated.

 The MIC value was 25 ppm, and the growth was inhibited at a very low concentration.

On the other hand, the growth inhibitory effect on aerobic bacteria was examined as follows.

That is, the bacteria were separated from the armpit by the stamp method. The aerobic indigenous staphylococci shown in Table 1 were obtained by culturing on a bouillon agar medium (manufactured by Far Eastern Pharmaceuticals) at 32 ° C. for 72 hours, and selecting cocci from the colonies that appeared. . Staphylococcus epidermidis, Micrococcus
Species (Micrococcus sp.) Were isolated and identified.

Staphylococcus aureus (Stap
hylococcus aureus), and the like.
The growth inhibitory effect of ferdinol on bacteria was evaluated by measuring the minimum growth inhibitory concentration (MIC).

 As a result, the effects were as shown in Table 1 below.

As described above, it was revealed that the antibacterial agent containing ferdinol selectively exhibited extremely high antibacterial activity against Gram-positive anaerobic bacteria, compared with the previously reported effects on aerobic bacteria and the like. .

 No report has been made on this point in the past.

Example 2 Inhibitory effect on bacteria causing caries Using BHI agar medium (Eiken) as a medium, ferruginol was examined for Streptococcus mutans ATC, a gram-positive anaerobic bacterium.
The antimicrobial activity was evaluated by measuring the minimum inhibitory concentration (MIC) for C 25175).

 The MIC value was 5 ppm, indicating a very strong antibacterial activity.

Next, examples of the skin external preparation according to the present invention will be described.

In addition, the skin external preparations of each Example also have excellent prevention and prevention of skin diseases derived from gram-positive anaerobic bacteria such as acne vulgaris.
The improvement effect was shown.

Example 3 Lotion (1) Ferdinol 0.01 (2) Glycerol 2.0 (3) 1,3-butylene glycol 2.0 (4) Sodium citrate 0.1 (5) Ethanol 10.0 (6) Polyoxyethylene oleyl alcohol 0.5 (7) Paraben 0.1 (8) Remaining purified water (Preparation method) The above components (1), (5), (6) and (7) are mixed and dissolved at room temperature, and the components (2) and (3) are also mixed and dissolved at room temperature. , (4) and (8) were added by stirring to obtain a lotion.

 Next, a comparative example will be described.

A lotion according to a comparative example was obtained in the same manner as in Example 3 except that ferruginol as the component (1) was omitted in Example 3.

The antibacterial effect on the Propionibacterium acnes of the lotion of Example 3 and Comparative Example was measured as follows.

Using Nissui's GAM agar medium as the medium, pH 7.3 ± 0.1
Then, the mixture was heated in an autoclave at 115 ° C. for 15 minutes to obtain flat plate agar. A 0.05 ml sample is placed on an 8 × 8 mm filter paper, adhered to a GAM agar medium in which Propionobacterium acnes standard strain (ATCC 11827) has been inoculated and dispersed in advance, and subjected to anaerobic culture at 37 ° C. for 3 days. The diameter of the transparent zone (propionibacterium acnes growth inhibition zone) corresponding to the periphery of the filter paper was measured, and the antibacterial activity was measured.

 The results are shown in Table 2 below.

As is clear from the results in Table 2, ferruginol
In Example 3 containing 0.01%, the diameter of the growth preventing zone was 1.5 times larger than that of the comparative example, indicating that the antibacterial activity was strong.

Example 4 Cleansing foam (1) Ferdinol 0.01 (2) Glycerin 13.0 (3) Palmitic acid 10.0 (4) Stearic acid 10.0 (5) Myristic acid 12.0 (6) Lauric acid 4.0 (7) Oleyl alcohol 1.0 (8) Hydroxide Potassium 6.0 (9) Purified water Remainder (Preparation method) Add component (8) to component (9) and heat. Add component (2) to this and immediately heat to 70 ° C, then heat and melt simultaneously. Components (1), (3),
(4), (5), (6) and (7) were added gradually with stirring. After addition, keep the temperature around 70 ° C for a while,
The saponification reaction was terminated to obtain a cleansing foam.

Example 5 Acne cream (1) Ferdinol 0.2 (2) Photosensitizer 201 0.003 (3) 1,3-butylene glycol 5.0 (4) Beeswax 2.0 (5) Cetanol 4.0 (6) Reduced lanolin 10.0 (7) Squalane 30.0 (8) Paraben 0.2 (9) Paraoxyethylene monosorbitan monolaurate 2.0 (10) Remaining purified water (Preparation method) The component (3) was added to the component (10), and the mixture was heated and maintained at 70 ° C (aqueous phase). Mix other ingredients, heat and dissolve to 70 ° C
(Oil phase). This oil phase was added to the aqueous phase to perform preliminary emulsification, and then uniformly emulsified with a homomixer to obtain an o / w cream.

Example 6 Pack (1) Ferdinol 1.0 (2) Vinyl acetate resin emulsion 12.0 (3) Polyvinyl alcohol 10.0 (4) Olive oil 3.0 (5) Sorbit 5.0 (6) Titanium oxide 15.0 (7) Ethanol 10.0 (8) Paraben 0.1 ( 9) Remaining purified water (Preparation method) The component (5) is mixed with the component (9), the components (6) and (2) are added thereto, and the component 3 is added to the component (7).
Was added, and heated to 70 ° C. to dissolve. Next, the components (1) and (8) were added to and mixed with the remaining component (7). Finally, the component (4) was added and the mixture was cooled to obtain a pack.

Example 7 Foundation (1) Ferdinol 0.05 (2) Titanium oxide 13.0 (3) Colloidal kaolin 25.0 (4) Talc 44.85 (5) Bengala 0.8 (6) Yellow iron oxide 2.5 (7) Black iron oxide 0.1 (8) Liquid paraffin 8.0 (9) Sorbitan sesquioleate 3.5 (10) Glycerin 2.0 (11) Paraben 0.2 (Production method) The above components (2) to (7) were mixed and pulverized through a pulverizer to an average particle size of 1 to 5 μm. This was transferred to a high speed blender, and component (10) was added and mixed. Separately, component (1),
(8), (9) and (11) were mixed and made uniform, and the above mixture was added thereto, and further mixed uniformly. This was processed by a pulverizer, and after uniforming the particle size, compression molding was performed to obtain a cake-type foundation.

Example 8 Emulsion (1) Ferdinol 0.2 (2) Liquid paraffin 10.0 (3) Vaseline 4.0 (4) Stearic acid 2.0 (5) Cetanol 1.0 (6) Glycerin monostearate (self-emulsifying type) 2.0 (7) Propylene glycol 7.0 (8) Purified water Remainder (9) Sodium hydroxide 0.4 (Production method) Components (1) to (6) are mixed, and after heating and dissolving, kept at 70 ° C (oil phase). After mixing and dissolving the components (7) to (9),
Keep at ° C (aqueous phase). The oil phase was added to the aqueous phase, and then uniformly emulsified with a homomixer, and cooled to 30 ° C. while stirring well to obtain an emulsion.

Oral composition Next, examples of the oral composition according to the present invention will be described.

In addition, the oral composition of each Example also showed an excellent preventive and ameliorating effect on periodontal disease derived from gram-positive anaerobic bacteria such as caries.

Example 9 Toothpaste (1) Sorbitol 20.0 (2) Silicic anhydride 50.0 (3) Sodium polyacrylate 0.7 (4) Sodium lauryl sulfate 1.8 (5) Triethanolamine 0.5 (6) Saccharin sodium 0.1 (7) Paraoxybenzoic acid Methyl 0.2 (8) Perfume 0.9 (9) Hinokitiol 0.2 (10) Ferdinol 0.5 (11) Remaining purified water (Preparation method) The pH was adjusted to 7 by a conventional method to prepare toothpaste.

Example 10 Toothpaste (1) Propylene glycol 20.0 (2) Silicic anhydride 50.0 (3) Sodium polyacrylate 0.7 (4) Sodium lauryl sulfate 1.8 (5) Triethanolamine 0.5 (6) Saccharin sodium 0.1 (7) Paraoxybenzoate Methyl acid 0.1 (8) Fragrance 0.9 (9) Hinokitiol 0.2 (10) Ferdinol 0.1 (11) Purified water Remainder (Production method) The pH was adjusted to 7 by a conventional method to produce toothpaste.

Example 11 Toothpaste (1) Glycerin 20.0 (2) Sorbitol 50.0 (3) Dibasic calcium phosphate 0.7 (4) Carrageenan 1.0 (5) Sodium lauryl sulfate 1.2 (6) Sodium saccharin 0.2 (7) Fragrance 0.9 (8) Ferdinol 0.5 ( 9) Remaining purified water (Preparation method) The pH was adjusted to 8 by a conventional method to produce toothpaste.

Example 12 Toothpaste (1) Glycerin 20.0 (2) Sorbitol 20.0 (3) Dibasic calcium phosphate 30.0 (4) Carrageenan 1.0 (5) Sodium lauryl sulfate 1.2 (6) Saccharin sodium 0.2 (7) Fragrance 0.9 (8) Ferdinol 0.5 ( 9) Remaining purified water (Preparation method) The pH was adjusted to 8 by a conventional method to produce toothpaste.

Example 13 Mouthwash (1) Ethyl alcohol 20.0 (2) Polyoxyethylene (20 mol) sorbitan laurate 1.0 (3) Polyoxyethylene (40 mol) hydrogenated castor oil 0.5 (4) Ferdinol 0.5 (5) Sodium hydroxide 0.05 (6) Saccharin sodium 0.05 (7) Fragrance 0.5 (8) Remaining purified water (Preparation method) The pH was adjusted to 8 by a conventional method to produce a mouthwash.

Example 14 Mouthwash (1) Ethyl alcohol 30.0 (2) Polyoxyethylene (20 mol) sorbitan laurate 1.0 (3) Polyoxyethylene (40 mol) hydrogenated castor oil 0.5 (4) Ferdinol 0.5 (5) Sodium hydroxide 0.05 (6) Saccharin sodium 0.05 (7) Fragrance 0.5 (8) Remaining purified water (Preparation method) The pH was adjusted to 8 by a conventional method to produce a mouthwash.

[Effects of the Invention] The present invention is configured as described above, and has the following effects.

According to the antibacterial agent for gram-positive anaerobic bacteria according to claim 1, since it contains ferruginol, it has an extremely high antibacterial property selectively against gram-positive anaerobic bacteria.

According to the skin external preparation of the second aspect, since it contains ferruginol, it is extremely effective against skin diseases derived from gram-positive anaerobic bacteria such as acne vulgaris.

According to the oral composition of the third aspect, since it contains ferruginol, it is extremely effective against various periodontal diseases derived from gram-positive anaerobic bacteria such as caries.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 7/40 A61K 7/40 // A61K 7/26 7/26 35/78 35/78 XB C07C 39/17 C07C 39/17

Claims (3)

(57) [Claims] 1. An antibacterial agent for gram-positive anaerobic bacteria, comprising ferdinol. 2. An external preparation for skin, comprising ferdinol. 3. An oral composition comprising ferdinol.