JP2003137792A - Water-soluble polymeric antifungal agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an antifungal compound that has low skin permeability, low irritation and is soluble in water, thus can be used in external preparations for skin and detergent compositions. SOLUTION: The external preparations for skin and the detergent compositions contain a water-soluble copolymer prepared from an antifungal monomer and a certain kind of water-soluble monomer.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a skin external preparation or cleansing composition containing an antibacterial polymer.

[0002]

2. Description of the Related Art In recent years, with increasing consumer interest in skin irritation of external preparations such as pharmaceuticals and cosmetics, development of raw materials with less irritation is desired. Most skin irritation occurs when the raw material penetrates the stratum corneum of the skin surface and penetrates inside. The antibacterial agent is necessary for storing the external preparation and the cleaning composition, but it is not necessary for the antibacterial agent to penetrate into the skin, and it is desirable that it does not penetrate into the skin from the viewpoint of irritation. One of the solutions is to increase the molecular size of antibacterial agents etc. and reduce skin permeability.

For example, as an ultraviolet absorber, a polymer obtained by polymerizing a monomer having an ultraviolet absorbing group has been proposed (JP-A-3-220213, JP-A-6-73369, JP-A-10). No. 231467, Japanese Patent Laid-Open No. 10-231468).

Regarding the antibacterial agents, there are those called antibacterial active polymers or polymeric antibacterial agents aiming at low toxicity and low irritation, and polycation type antibacterial agents have been studied (antibacterial and antifungal Vol. 23, No. 2, p87, 1995). But,
The cationic antibacterial agent has a problem that the preparations that can be used are limited because the effect thereof disappears due to the presence of salt.

From the above findings, poly-p-vinylphenol is considered as a promising nonionic antibacterial polymer (antibacterial and antifungal vol.8, No.9, p1, 1980). However, this compound has extremely low solubility in water, and the dosage form in which an effective amount can be incorporated is limited to a narrow range such as a high solvent concentration or an emulsion.

[0006]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide an antibacterial compound which is incorporated into an external preparation or a cleaning composition, has low skin permeability, is hypoallergenic and has water solubility. And

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have obtained an excellent antibacterial and water-soluble balance by copolymerizing a water-soluble monomer with an antibacterial monomer. We succeeded in synthesizing a mild antibacterial agent. More specifically, the present inventors have found that an antibacterial monomer having both a molecular structure having antibacterial activity and a polymerizable molecular structure, and a certain kind of antibacterial monomer having a molecular structure imparting water solubility and a polymerizable molecular structure. The present invention has been found to be possible to obtain an antibacterial compound having a low irritation and water solubility by copolymerizing with a water-soluble monomer.

That is, the present invention relates to a skin external preparation and a cleansing composition containing a copolymer containing an antibacterial monomer and a water-soluble monomer as polymerization components. Further, in the present invention, the antibacterial monomer constituting the above copolymer is preferably a monomer represented by the following general formula (I),

[Chemical 5] (Here, n = 0 to 6, X represents a hydrogen atom or a halogen atom.) The water-soluble monomer is preferably represented by the following general formula (II).

[Chemical 6] (Here, R ¹ is hydrogen or a methyl group, R ² is either an alkyl group or a phenyl group, and n is an integer of 1 to 30.)

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The antibacterial monomer constituting the compound of the present invention is a compound having both a molecular structure having antibacterial activity and a polymerizable molecular structure. The molecular structure having antibacterial activity is, for example, quaternary ammonium salt, biguanide,
Examples of the functional group include a phosphonium salt, a pyridinium salt, phenol, benzoic acid, 2-hydroxy-2,4,6-cycloheptatrienone, stipitato acid, and a polyhydric alcohol. Examples of the polymerizable molecular structure include functional groups composed of ethylene, propene, an amino group, a carboxyl group and the like.

Typical examples of the above-mentioned monomer include, for example, general formula (I)

[Chemical 7] (Where n = 0 to 6 and X represents a hydrogen atom or a halogen atom). Furthermore, p-vinylphenol is particularly preferable.

The water-soluble monomer constituting the compound of the present invention is a compound having both a water-soluble molecular structure and a polymerizable molecular structure. Examples of the water-soluble molecular structure include a functional group including a hydroxyl group, polyethylene glycol, polypropylene glycol and the like. Examples of the polymerizable molecular structure include functional groups composed of ethylene, propene, an amino group, a carboxyl group and the like.

Typical examples of the above-mentioned monomer include, for example, the general formula (II)

[Chemical 8] (Wherein R ¹ is hydrogen or a methyl group, R ² is either an alkyl group or a phenyl group, and n is an integer of 1 to 30). Furthermore, polyethylene glycol methyl ether methacrylate is particularly preferable.

The method for producing the copolymer of the present invention may be carried out by a conventional method, in which the monomer represented by the general formula (I) and the monomer represented by the general formula (II) are used as a polymerization initiator in a solvent. It is obtained by reacting in the presence. The copolymer of the present invention preferably contains substantially no oligomers such as monomers, dimers and trimers. In the present invention, the phrase "substantially free of monomer, dimer and trimer" means that the content of the monomer, dimer and trimer is 3% or less. When monomers, dimers and trimers, and other impurities remain in the obtained copolymer, they can be purified by a conventional method such as a reprecipitation method, an extraction method or a fractionation method.

The molecular weight of the copolymer of the present invention is not particularly limited, but the number average molecular weight is preferably 1,000 or more, and particularly preferably 2,500 or more in order to exhibit the effect of reducing skin irritation. From the viewpoint of reducing skin irritation, a higher molecular weight is preferable, but since the antibacterial activity decreases with an increase in molecular weight, 100,000 or less, particularly 50,000 or less is preferable. For example, the molecular weight of the copolymer of the present invention is preferably 1,000 to 100,000,
Particularly preferably, 2,500 to 50,000 can be selected.

The copolymer of the present invention may be a random copolymer or a block copolymer. The ratio of the antibacterial monomer is generally 5 to 90 mol% of the whole copolymer,
Preferably 20-80 mol%, more preferably 40-8
It is 0 mol%. In addition, the present invention contains, in addition to the antibacterial monomer and the water-soluble monomer, one or more kinds of monomers, if necessary, as a third copolymer component within a range that does not impair the effects of the present invention. You can Examples of the copolymerizable monomer include N, N-dimethylaminopropylacrylamide, N-vinylpyrrolidone, N-isopropylamide, and 2-methacryloyloxyethylphosphorylcholine. The content of the third monomer component is 60 mol% or less, preferably 40 mol% or less based on the whole.

The polymer of the present invention is widely applicable to cosmetics, detergents, pharmaceuticals, quasi-drugs and the like applied to the outer skin as a component having low skin irritation, and its formulation is an aqueous solution type,
Solubilization system, emulsion system, powder system, oil system, gel system, ointment system,
Aerosol system, water-oil 2-layer system, water-oil-powder 3-layer system, etc.
Can take a wide range of dosage forms. That is, basic cosmetics can be widely applied in the above-mentioned dosage forms in the form of facial cleansers, lotions, milky lotions, creams, gels, essences (cosmetics), packs / masks, shaving cosmetics, and the like. is there. Further, as long as it is a drug or a quasi drug, it can be widely applied to various forms such as ointments. The dosage forms and forms that the polymer of the present invention can take are not limited to these dosage forms and forms.

In the present invention, generally known base components may be widely used and blended in accordance with the above-mentioned desired dosage form and form within a range in which the intended effect of the present invention is not impaired by the blending thereof. it can. That is, olive oil, avocado oil, rice bran oil, grape seed oil, macadamia nut oil,
Natural animal and vegetable oils and fats such as corn oil, rapeseed oil, castor oil, sunflower oil, coconut oil, squalene, beef tallow, horse oil and egg yolk oil; jojoba oil, beeswax, candelilla wax, carnauba wax, lanolin and other waxes; polybutene, Hydrocarbons such as squalane, liquid paraffin, paraffin and vaseline; fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, isostearic acid, linoleic acid, linolenic acid and hydroxystearic acid; cetanol , Higher alcohols such as stearyl alcohol, behenyl alcohol, octyldodecanol, cholesterol, phytosterol; isononyl isononanoate, isocetyl octanoate, octyldodecyl myristate, isopropyl palmitate, isocetate stearate. , Esters such as glyceryl tri-2-ethylhexanoate; silicone oils such as methylpolysiloxane, methylhydrogenpolysiloxane, decamethylcyclopentasiloxane, methylphenylpolysiloxane; ethylene glycol, glycerin, diglycerin, 1,3- Polyhydric alcohols such as butylene glycol and 1,2-pentanediol; saccharides such as sorbitol, mannitol, glucose, maltitol, etc .; high water solubility such as gum arabic, carrageenan, xanthan gum, guar gum, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer Molecules: Organic solvents such as ethanol; Powders of titanium dioxide, mica, talc, kaolin, titanium dioxide-coated mica, etc .; Polyoxyethylene octyldodecyl ether, Polyoxyethylene polyoxypropylene Nonionic surfactants such as lauryl ether, ethylene glycol monostearate, polyoxyethylene sorbitan tristearate, and polyoxyethylene hydrogenated castor oil; cationic surfactant interfaces such as stearyltrimethylammonium chloride, benzalkonium chloride, and laurylamine oxide. Activator: Anionic surfactant such as sodium palmitate, sodium laurate, potassium lauryl sulfate, alkylsulfuric acid triethanolamine ether, acylmethyl tauric acid; Antioxidant such as tocopherol, propyl gallate, ascorbic acid, citric acid Alternatively, antioxidant aids; menthol, peppermint oil, methyl salicylate and other cooling agents, dyes, fragrances, or purified water can be used in appropriate combination according to the formulation according to the desired dosage form. Specific formulation examples of the present invention will be described in Examples described later.

The synthesis examples of the polymer according to the present invention will be shown below, but the present invention is not limited thereto. Synthetic example Polyethylene glycol methyl ether methacrylate
(In the general formula (II), n is 8.5 on average) and t-butoxystyrene were subjected to radical copolymerization using AIBN as an initiator in a benzene solvent and dried under reduced pressure to synthesize a copolymer. Then, hydrochloric acid was added to the copolymer in a THF solvent, and the t-butoxy group was replaced with hydrogen to synthesize the target copolymer poly (p-vinylphenol-co-polyethylene glycol methyl ether methacrylate).

Measurement of Physical Properties The poly (p-vinylphenol-co-polyethylene glycol methyl ether methacrylate) obtained in the above synthesis example was a yellowish white viscous substance, and its structure was confirmed by ¹ H-NMR (FIG. 1). The molecular weight and the molecular weight distribution were measured by GPC (gel permeation chromatography) (Fig. 2).
In FIG. 2, the vertical axis represents the magnitude of the output signal obtained by measuring the molecular weight with a differential refraction detector, curve A is the GPC chromatogram of the sample, and curve B is the molecular weight calibration curve.
From the measurement results, the number average molecular weight in terms of polystyrene was 27.
60, the weight average molecular weight was 4824, the ratio of residual monomers and low molecular weight components such as dimers and trimers was 1.44% by weight, and it was confirmed that a polymer without low molecular weight components could be synthesized. .

Water -Solubility Confirmation The homopolymer of p-vinylphenol does not show water solubility at all, whereas the poly (p-vinylphenol-co-polyethylene glycol methacrylate) obtained in the above Synthesis Example has at least 10 It was confirmed that a colorless and transparent aqueous solution could be prepared up to a weight percentage.

Measurement of antibacterial activity USP XXII challenge for antibacterial activity of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli of 5% by weight aqueous solution of poly (p-vinylphenol-co-polyethylene glycol methyl ether methacrylate) obtained in the above synthesis It was evaluated by the test method. As a comparative example, a solution containing no antibacterial agent,
The antibacterial activity of methylparaben, which is generally known as an antibacterial agent, was also measured (Table 1).

[0022] From the results, the compound of the present invention, like the conventional antibacterial agent,
It was found that it showed sufficient antibacterial activity against many bacteria.

Measurement of irritation Using a three-dimensional cultured skin model (LSE-High, manufactured by Toyobo Co., Ltd.), a toxicity test on human fibroblasts was performed.
In the test, an aqueous solution of the test substance was applied to the cultured skin for a predetermined time. After that, the living cells were treated with MTT (3- (4,5-dimethylthiazol-2-
yl) -2,5-diphenyltetrazolium bromide), which is the concentration showing the 50% viability of cells (EC ₅₀ value) using the MTT assay method, which determines the cell viability from the intensity of the blue-purple color emitted by the product when absorbed and decomposed. ) Was calculated (Table 2).

[0024] The compound of the comparative example was confirmed to kill half of the cells at each concentration, but the compound of the example did not show any cell death even at a concentration of 1%. from this result,
The compounds of the present invention include methylparaben and p- which is a monomer.
It was confirmed that the irritation inside the skin was significantly reduced as compared to vinylphenol.

Next, examples of blending the external preparation for skin and the cleaning composition containing the mild antibacterial polymer antibacterial agent of the present invention will be shown.

Formulation 1 "Lotion" (Component) (wt%) Sodium citrate 0.1 Sodium pyrrolidonecarboxylate 1.0 BG 5.0 Purified water Total amount of hypoallergenic polymeric antibacterial agent obtained in Synthesis Example 0.5 (production method) at 50 ° C. Dissolve ingredients by heating and stir 30
Cool to ° C.

Formulation 2 "O / W emulsion" (component) (wt%) Microcrystalline wax 1.0 Beeswax 2.0 Adsorbed purified lanolin 2.0 Liquid isoparaffin 30.0 Sorbitan sesquioleate 4.0 Polyoxyethylene sorbitan monooleate (20E) .O.) 1.0 Aluminum stearate 0.2 Hypoallergenic polymer antibacterial agent obtained in Synthetic Example 0.4 Glycerin 8.0 Purified water Remainder (production method) Glycerin was added to purified water and mixed and heated to 70 ° C.
And Other ingredients are melted by heating to 70 ℃. The above-mentioned aqueous phase component is gradually added to this oil phase component while stirring, and then uniformly emulsified by a homogenizer. After emulsification, cool to 30 ° C with a heat exchanger.

Formulation 3 "Bath cream" (Components) (wt%) Sodium N-acyl-L-glutamate 25.0 Palmitic acid 3.0 Polyoxyethylene polyoxypropylene glycol 5.0 Glycerin 20.0 Maltitol 15.0 Low obtained in the synthesis example Stimulating macromolecule antibacterial agent 0.4 Purified water balance (manufacturing method) Glycerin and maltitol were added to purified water to 70 ℃
Heat to. To this, sodium N-acyl-L-glutamate is added and dissolved (aqueous phase). On the other hand, palmitic acid and polyoxyethylene polyoxypropylene glycol, which have been heated and dissolved in advance, are added to the above-mentioned aqueous phase, mixed and stirred, and after deaeration, stirred and cooled to 30 ° C. by a heat exchanger.

No deposition of a mild polymer antibacterial agent was observed in any of the external preparations and cleaning compositions even after standing at room temperature for 3 months, and stable external preparations and cleaning compositions could be produced.

[0030]

The compound of the present invention has an antibacterial activity against various bacterial species, has low skin permeation, and is excellent in safety to the skin. Therefore, it is extremely useful as an external preparation for skin, an antibacterial agent for cleaning compositions and an antiseptic agent. It is useful.

[Brief description of drawings]

FIG. 1 Poly (p-vinylphenol-co-polyethylene glycol methyl ether methacrylate) obtained in the synthesis example
The NMR spectrum of is shown.

FIG. 2 Poly (p-vinylphenol-co-polyethylene glycol methyl ether methacrylate) obtained in the synthesis example
3 shows the gel permeation chromatography of.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ identification code FI theme code (reference) A61K 7/00 A61K 7/00 M 4J100 N 7/40 7/40 7/50 7/50 A61P 17/00 101 A61P 17/00 101 C08F 212/14 C08F 212/14 220/26 220/26 290/06 290/06 C11D 3/37 C11D 3/37 (72) Inventor Yuka Hori 2 Shirite, Tsurumi-ku, Yokohama-shi, Kanagawa Chome 3-6 Hokushin Kogyo Co., Ltd. (72) Inventor Shoko Matsukuma 12-13, Shinjino, Totsuka-ku, Yokohama-shi, Kanagawa Inside FANCL Central Research Institute (72) Inventor Tatsu Miyamoto Kamishinano, Totsuka-ku, Yokohama-shi, Kanagawa No. 12 No. 13 F-term in FANCL Central Research Institute Co., Ltd. (reference) 4C083 AA082 AC012 AC022 AC112 AC122 AC132 AC242 AC302 AC612 AC662 AD052 AD091 AD092 AD512 CC04 CC05 CC23 DD23 DD27 DD33 EE01 E E10 EE12 FF01 FF05 4C086 AA01 AA02 FA02 FA06 MA01 MA04 NA03 NA07 NA08 NA14 ZA90 4H003 AB03 AB09 AC23 BA12 DA02 EB04 EB05 EB30 ED02 FA02 FA34 4H011 AA02 BA01 AC08 BA07Q08Q08BA08Q08Q07Q07Q08Q07Q07Q08QQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQFF BC43Q CA04 JA50 JA53

Claims (6)

[Claims] 1. A skin external preparation containing a copolymer containing an antibacterial monomer and a water-soluble monomer as polymerization components. 2. The external preparation for skin according to claim 1, wherein the antibacterial monomer is a monomer represented by the following general formula (I). [Chemical 1] (Here, n = 0 to 6, X represents a hydrogen atom or a halogen atom.) 3. The external preparation for skin according to claim 1, wherein the water-soluble monomer is represented by the following general formula (II). [Chemical 2] (Here, R ¹ is hydrogen or a methyl group, R ² is either an alkyl group or a phenyl group, and n is an integer of 1 to 30.) 4. A detergent composition containing a copolymer containing an antibacterial monomer and a water-soluble monomer as polymerization components. 5. The cleaning composition according to claim 4, wherein the antibacterial monomer is a monomer represented by the following general formula (I). [Chemical 3] (Here, n = 0 to 6, X represents a hydrogen atom or a halogen atom.) 6. The detergent composition according to claim 4, wherein the water-soluble monomer is represented by the following general formula (II). [Chemical 4] (Here, R ¹ is hydrogen or a methyl group, R ² is either an alkyl group or a phenyl group, and n is an integer of 1 to 30.)