JP5372573B2 - Antibacterial agent and preparation comprising the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug which shows more improved safety without detriment to antibacterial power with a view to solve the problem that skin antibacterial agents now generally used produce allergies, skin irritation, and the like. <P>SOLUTION: There are provided a highly safe antibacterial agent comprising an &alpha;-mono-p-hydroxyphenyl ethyl glyceryl ether and a cosmetic, a liquid drug, a quasi-drug, and a food containing the same as a preservative. According to this invention, the antibacterial agent has excellent safety and sufficient antibacterial action, so that it can achieve products, for example, cosmetics, drugs, quasi-drugs, and foods, which are powerful for protecting microbial contamination without using a conventionally used paraoxybenzoic acid ester (paraben) in combination and being excellent in safety. <P>COPYRIGHT: (C)2011,JPO&amp;INPIT

Description

The present invention relates to an antibacterial agent, and α-mono p-hydroxyphenylethyl glyceryl ether, which is a novel compound, has a high antibacterial action. Mixing can be expected. In addition, the antibacterial action of α-mono p-hydroxyphenylethyl glyceryl ether can be utilized as a preservative for pharmaceuticals, quasi drugs and liquid drinks.

Antibacterial agents are used for the purpose of suppressing the growth of microorganisms mixed from the outside and preventing the product from deteriorating over time in products that are used repeatedly after opening the skin, especially cosmetics, etc. . As a representative one, paraoxybenzoic acid esters are widely used. In particular, paraoxybenzoic acid esters are widely used in foods, but due to the fact that past allergies have been observed and skin irritation problems have been pointed out, the upper limit of the amount to be added to cosmetics is limited. It is prescribed. In addition, benzoate, salicylate and dehydroacetate are often used, but skin irritation problems have been pointed out as with paraoxybenzoate.

In particular, cosmetics have recently moved to antibacterial properties with phenoxyethanol, but the problem of skin irritation cannot be avoided. As natural antibacterial substances, hinokitiol, monocaprylic acid glycerides, cationic amino acid derivatives, bisabolol, glycols, rosemary extract and grapefruit seed extract as plant extracts are known. It has also been tried to suppress the growth of microorganisms by using them together. However, hinokitiol is known to brown in the presence of iron ions. Glyceryl monocaprylate generates caprylic acid liberated by hydrolysis of the ester bond in the presence of water by hydrolysis. As a result, it causes odor. Moreover, in the plant extract antibacterial agent, since the active ingredient is not sufficiently determined, the antibacterial activity varies from lot to lot and it is difficult to maintain a certain antibacterial property. From such a viewpoint, development of a new antibacterial agent that clears these various problems is demanded. Among them, 1,2-octanediol having a glycol structure (Patent Literature 1, Non-Patent Literature 1), α-2 ethylhexyl glyceryl ether (Patent Literature 2, Patent Literature 3, Non-Patent Literature 2) and a tyrosol derivative ( Patent document 4) has been developed.

Japanese Patent No. 3615218 JP 2004-43336 A JP 2007-29049 A JP 2007-39340 A

Fragrance Journal Vol.34, No.4, 34-38 (2006) Fragrance Journal Vol.34, No.4, 39-46 (2006)

It is the present invention to provide a highly safe antibacterial agent having a wide range of antibacterial properties similar to paraoxyxybenzoic acid, and to provide a product with excellent safety by blending it with a product that requires antiseptic power. It is a problem.

Therefore, as a result of intensive studies in view of such circumstances, the present inventors have found that α-mono p-hydroxyphenylethyl glyceryl ether has a low concentration and a wide antibacterial spectrum among the compounds having a glycol structure and a hydrophobic group structure. The headline, the present invention has been completed.

That is, the present invention is an antibacterial agent composed of α-mono p-hydroxyphenylethyl glyceryl ether represented by the general formula 1, and a skin external preparation, a pharmaceutical product, a quasi-drug, a food and a liquid beverage comprising the same. .

Hereinafter, the configuration of the present invention will be described in detail.
The α-mono p-hydroxyphenylethyl glyceryl ether of the present invention is a compound having an ether bond at the α-position of tyrosol and glycerin, which is known as an anti-inflammatory component in olive, and has a hydrophilic group having a function as a moisturizer in the structure It has a glycol structure.

The synthesis of α-mono p-hydroxyphenyl ethyl glyceryl ether can be obtained by a general production method of α-monoalkyl glyceryl ether. It protects the hydroxy group of tyrosol and reacts with glycidol to selectively form an ether linkage at the α-position. Thereafter, the protecting group can be removed to obtain the desired product.

The α-mono p-hydroxyphenylethyl glyceryl ether of the present invention alone exhibits sufficient antibacterial properties, but a small amount of phenoxyethanol, hinokitiol, monocaprylic acid glyceride, cationic amino acid derivatives, bisabolol and 1,2-pentanediol, By using a combination of an antibacterial agent such as 1,2-hexanediol, a plant extract having an antibacterial action, or a chelating agent such as EDTA, an improvement in the antibacterial action can be expected.

In addition to the above-mentioned essential components, the antibacterial agent of the present invention includes other components used for normal cosmetics, pharmaceuticals, quasi drugs, etc. within the range that does not interfere with the antibacterial action, such as vitamin B2 and vitamin B6. , Vitamin C, vitamin D, nicotinic acid, vitamin E, vitamin P, vitamins such as biotin, amino acids and amino acid derivatives, jojoba oil, oil such as squalane, glycerin, sorbitol, 1,3-butylene glycol, etc. Glycols, collagen, hyaluronic acid and other polymer moisturizers, antioxidants, surfactants, anti-inflammatory agents such as glycyrrhizic acid derivatives, various plant extracts, thickeners such as carboxyvinyl polymer, fragrance, water, alcohol In addition, resin powders such as colorants and polyethylene can be appropriately blended as necessary.

Although it is the compounding quantity with respect to the product of (alpha) -mono p-hydroxyphenyl ethyl glyceryl ether concerning this invention, when it mix | blends with the example of cosmetics, for example, according to the embodiment of cosmetics, the usage form of cosmetics, etc. Although it can be varied and is not particularly limited, in principle, an effective amount may be present in the cosmetic, but the general blending amount is 0.0001 to 5% by mass in the cosmetic composition, Preferably it is 0.01-2 mass%, More preferably, it is 0.05-0.5 mass%, but it is a standard because an appropriate amount cannot be specifically limited by the dosage form and prescription content of cosmetics.

The range of application to the cosmetic according to the present invention is not limited by the dosage form, and can be applied to all cosmetics. The same applies to liquid medicines, quasi drugs and food drinks.

For example, α-mono p-hydroxyphenylethyl glyceryl ether according to the present invention can be used in various internal and external preparations (including preparations used for animals), specifically, ampoules, capsules Pills, tablets, powders, granules, solids, liquids, gels or bubbles 1) pharmaceuticals, 2) quasi drugs, 3) foods, 4) topical or systemic Skin cosmetics, 5) Medicinal or / and cosmetic preparations applied to the scalp and hair (eg shampoos, rinses, treatments, permanent liquids, hair dyes, hair styling agents, hair styling agents, hair growth and hair restorations 6) Bathing agents used in bath water, 7) In addition, liquid odor / deodorant, hygiene products, sanitary cotton, wet tissue, etc.
In addition, liquid beverages include pharmaceutical and quasi-drug nutrition drinks, general food fruit juices, vegetable juices, whey drinks, soft drinks, alcoholic beverages, and other general beverages such as health foods. Increased use.

According to the present invention, an antibacterial agent having a wide antibacterial action and excellent safety can be provided by an antibacterial agent comprising α-mono p-hydroxyphenylethyl glyceryl ether. Further, by using the antibacterial agent of the present invention, it is possible to provide a product having sufficient antibacterial action without using a paraoxybenzoic acid ester and having excellent safety.

Comparison of cytotoxicity between Example 1 and general-purpose antibacterial agents

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited to an Example.
[Production of α-mono p-hydroxyphenylethyl glyceryl ether]
First, production examples of α-mono p-hydroxyphenylethyl glyceryl ether which is characteristic in the external preparation for skin according to the present invention will be described.

“Α-Mono p-hydroxyphenylethyl glyceryl ether” 3- (2- (4-hydroxyphenyl) -1,2-propanediol
A mixture of P-hydroxyphenylethyl alcohol, benzyl chloride and K ₂ CO ₃ was heated to reflux in acetone for 6 hours. The solvent was removed, ethyl acetate and water were added for liquid separation, and the organic layer was washed with 10% NaOH and then with water, dehydrated and concentrated. The residue was recrystallized from ethyl acetate to give 2- (4-phenoxyphenylethanol).
400 MHz ¹ H
NMR (CDCl ₃ , 30 ° C) 2.81 (t, 2H, J = 6.6 Hz, -CH ₂ CH ₂ OH),
3.83 (t, 2H, J = 6.6 Hz, -CH ₂ CH ₂ OH),
5.05 (s, 2H, -OCH ₂ Ar-), 6.91 (d, 2H, J = 8.4 Hz, ArH), 7.14 (d, 2H, J = 8.4 Hz, ArH),
7.30-7.44 (m, 5H, ArH).
A mixture of 2- (4-phenoxyphenylethanol) (2.8 mmol, 638 mg), glycidol (14.0 mmol, 1034 mg), K2CO3 (0.14 mmol, 19 mg) was stirred at 130 ° C. for 6 h. did. Ethyl acetate and water were added for liquid separation, and the organic layer was dehydrated, concentrated and dried under reduced pressure to obtain a crude product (583 mg). This crude product (300 mg) was subjected to GPC fractionation to give 3- (2- (4-phenoxyphenyl))-1,2-propanediol (55 mg).
400 MHz ¹ H
NMR (CDCl ₃ , 30 ° C) 2.83 (t, 2H, J = 6.8 Hz, -Ar-CH ₂ CH _2- ), 3.48-3.83 (m, 7H)
5.04 (s, 2H, -OCH ₂ -Ar), 6.90 (d, 2H, J = 8.4 Hz, ArH), 7.12 (d, 2H, J = 8.4 Hz, ArH),
7.31-7.44 (m, 5H, Ar-H).
EtOH (5 ml) was added to 3- (2- (4-phenoxyphenyl))-1,2-propanediol (0.4 mmol, 126 mg) and Pd—C (50 mg). Stir for 7 h. Pd—C was filtered, washed with hot EtOH, concentrated and dried under reduced pressure, α-mono p-hydroxyphenylethylglyceryl ether [3- (2- (4-hydroxyphenyl) -1,2-propanediol) ( 76 mg, 86%).
400 MHz ¹ H
NMR (CDCl ₃ , 30 ° C) 2.82 (t, 2H, J = 7.0 Hz, -Ar-CH _2- ),
3.49-3.82 (m, 7H), 6.76 (d, 2H, J =
8.4 Hz, Ar-H), 7.07 (d, 2H, J = 8.4 Hz, Ar-H).

(Comparative Example 1)
p-phenethyl alcohol (100 mmol, 12.5 g), glycidol (20 mmol, 1.48 g), K2CO3 (1.0 mmol, 139 mg) at 130 ° C., 6
The mixture was stirred for h. Hot hexane was added to remove the soluble part, the insoluble part was subjected to Kugel distillation and vacuum distillation, and α-mono p-phenylethylglyceryl ether [3- (2- (4-phenyl) -1,2-propanediol) ( 1.00 g, 25%).
400 MHz ¹ H
NMR (CDCl ₃ , 30 ° C) 2.07 (t, 1H, J = 5.1 Hz, -OH),
2.52 (d, 1H, J = 5.1 Hz, -OH), 2.90 (t, 2H, J = 6.8 Hz, -Ar-CH _2- ),
3.49 ~ 3.85 (m, 7H), 7.20 ~ 7.32 (m, 5H, Ar-H)
125 MHz ¹³ C
NMR (CDCl ₃ , 30 ° C) 36.1 (ArCH ₂ ), 64.0 (-CH ₂ OH)
70.5 (-CHOH-), 72.3 (-OCH _2- ), 72.4 (-OCH _2- ), 126.3,
128.4, 128.8, 138.6.

(Comparative Example 2)
p-methoxyphenylethanol (40 mmol, 6.01 g), glycidol (20
mmol,
1.48
g), K2CO3 (0.5 mmol, 0.14 g) was stirred at 130 ° C. for 6 h. Warm hexane is added to remove unreacted substances as soluble parts, insoluble parts are distilled under reduced pressure, and α-mono p-methoxyphenylethylglyceryl ether 3- (2- (4-methoxyphenyl) -1,2-propanediol (1.10 g) was obtained.
400 MHz ¹ H
NMR (CDCl ₃ , 30 ° C) 2.14 (t, 1H, J = 5.1 Hz, -OH),
2.56 (d, 1H, J = 5.1 Hz, -OH), 2.83 (t, 2H, J = 6.6 Hz, -Ar-CH _2- ),
3.49 ~ 3.82 (m, 7H) 3.79 (s, 3H, -OCH ₃ ), 6.84 (d, 2H, J = 8.6 Hz, Ar-H), 7.12 (d, 2H, J = 8.6 Hz, Ar-H) .
125 MHz ¹³ C
NMR (CDCl ₃ , 30 ° C) 5.20 (ArCH ₂ ), 55.2
(-OCH ₃ ), 64.0 (-CH ₂ OH) 70.5 (-CHOH), 72.4 (-OCH _2- ),
72.6 (-OCH _2- ), 113.8, 129.7, 130.6, 158.1.

(Comparative Example 3)
p-Ethoxyphenethyl alcohol (10 mmol, 1.7 g), glycidol (5 mmol, 380 mg) and K2CO3 (0.5 mmol, 70 mg) were stirred at 130 ° C. for 6 h. Warm hexane was added to remove the raw material, and α-mono-p-ethoxyphenylethylglyceryl ether [3- (2- (4-ethoxyphenyl) -1,2-propanediol) as a distillate by Kugel distillation (200 ° C) ( 19%).
400 MHz ¹ H NMR (CDCl ₃ ,
30 ° C) 1.40 (t, 3H, J = 7.0 Hz, -CH ₃ ), 2.05 (t,
1H, J = 5.1 Hz, -OH), 2.49 (d, 1H, J = 5.1 Hz, -OH), 2.82 (t, 2H, J
= 7.0 Hz, -Ar-CH _2- ), 3.48 to 3.83 (m, 7H), 4.01 (q, 2H, J = 7.0 Hz, -CH ₂ CH ₃ ),
6.83 (d, 2H, J = 8.1 Hz, Ar-H), 7.10 (d, 2H, J
= 8.1 Hz, Ar-H)

(Experimental example)
[Confirmation of antibacterial activity (challenge test)]
In the α-mono p-hydroxyphenylethyl glyceryl ether, α-mono p-phenylethyl glyceryl ether, α-mono p-methoxyphenylethyl glyceryl ether and α-mono p-ethoxyphenylethyl glyceryl ether obtained by synthesis, An antibacterial confirmation test was conducted on five species of pharmacopeia preservative efficacy test (S. aureus, E. coli, Ps. Aerginosa, C. arbicans, A. niger). Samples were α-mono p-hydroxyphenyl ethyl glyceryl ether, α-mono p-phenyl ethyl glyceryl ether, α-mono p-methoxyphenyl ethyl glyceryl ether and α-mono p-ethoxyphenyl ethyl glyceryl ether, α-mono 2 -Ethylhexyl glyceryl ether (SENSIVA SC-50: manufactured by Schuke & Mayr), glyceryl monocaprate (MGK: manufactured by Nikko Chemicals), methyl paraoxybenzoate (methyl paraben), ethyl paraoxybenzoate and phenoxyethanol (ethyl paraben) 1, 2-Octanediol (manufactured by Tokyo Chemical Industry Co., Ltd.) was taken in a 7.0% 1,3-butylene glycol aqueous solution so that the amount of each sample was 0.10% by mass and subjected to the test. The initial concentration of the test bacteria is S. cerevisiae. aureus, E .; coli. , Ps. aerginosa is 1 × 10 ⁵ , C.I. arbicans, A.M. Niger performed at 10 × 10 ⁴ .

[Criteria]
After 1 day, 3 days, 7 days, 14 days, and 28 days, 1 mL was taken out from various samples, added to the culture medium, cultured according to the culture conditions of each microorganism, and the number of viable bacteria was confirmed. The numerical values in the table indicate the day when the target bacteria were killed, and those with the number of bacteria indicate the number of bacteria after 4 weeks.

Table 1 is a comparison of antibacterial activity of analogs of α-mono p-hydroxyphenylethyl glyceryl ether.

From the results in Table 1, the difference in antibacterial activity due to the difference in the functional group at the P position was confirmed. As a result, it was confirmed that the p-hydroxy compound was extremely excellent in antibacterial activity.

Table 2 is a comparison with general-purpose antibacterial agents.

From the results shown in Table 2, α-mono p-hydroxyphenylethyl glyceryl ether has a stronger antibacterial effect on bacteria than methyl paraoxybenzoate (methyl paraben) or monocaprylate glyceryl (C8 ester). It was found that it was comparable or slightly stronger than ethylhexyl glyceryl ether (C8 ether) and 1,2-octanetanediol (C8 diol). Regarding fungi, glyceryl monocaprate, 2-ethylhexyl glyceryl ether, and 1,2-octanediol tend to increase and show little efficacy. On the other hand, although death is not seen, in Example 1, as in the case of parabens, the number of bacteria decreased by 95.2% compared to the initial number of inoculations and greatly decreased to 4.8% of the original number. It was confirmed that the efficacy was similar. The compounds having a diol structure listed here are known to have antibacterial properties, but have a weak antibacterial property against mold. It was confirmed that α-mono p-hydroxyphenylethyl glyceryl ether of the present invention can be replaced with paraben.

"Antimicrobial activity in emulsion systems"
Antibacterial activity was confirmed against five bacterial species (S. aureus, E. coli, Ps. Aerginosa, C. arbicans, A. niger) in the Japanese Pharmacopoeia preservation efficacy test. Samples were prepared according to conventional methods, and the test was carried out for the composition emulsions described in Table 5, Examples and Comparative Examples.

From the results in Table 3, the antibacterial activity is strong against bacteria compared to the same concentration of glyceryl monocaprate (C8 ester), 2-ethylhexyl glyceryl ether (C8 ether) and 1,2-octanetanediol (C8 diol). It was confirmed that the antibacterial activity was comparable to that of parabens.

(Experimental example 3) [Confirmation of cytotoxicity]
96-well plate is seeded with Hela cells per well and grown in a CO2 incubator for 24 hours. Twenty-four hours after seeding, the sample is diluted serially (1/2) with medium and added. Next, it is grown in a CO2 incubator for 48 hours, 96 well
Discard the plate medium, wash with PBS (-), and then add a new WST reagent (Cell
100 μL each of those added with Counting Kit) is added. It is reacted for 2 hours in a CO2 incubator and after 2 hours the absorbance at 415 nm is measured with a microplate reader.

As shown in FIG. 1, it is expected that the cytotoxicity is weak and the irritation is low as compared with methylparaben and 2-ethylhexyl glyceryl ether (C8 ether).

Next, specific product examples using the α-mono p-hydroxyphenylethyl glyceryl ether according to the present invention will be described.

(Prescription example) The following is a prescription example of the present invention.
<Prescription Example 1> Lotion (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether ... 0.1
Glycerin ... 5.0
Polyoxyethylene sorbitan monolaurate (20E.0) ... 0.5
1,3-butylene glycol ... 5.0
1,2-pentanediol ... 2.0
Antioxidant ... proper amount perfume ... appropriate amount purified water ... the balance

<Formulation example 2> Cosmetic cream (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether ... 0.1
N-coconut oil fatty acid acyl L-alkenyl ethyl-DL-chlorocarbonate
Beeswax ... 2.0
Stearyl alcohol ... 5.0
Stearic acid 8.0
Squalane ... 10.0
Self-emulsifying glyceryl monostearate ... 3.0
Polyoxyethylene cetyl ether (20E.0) ... 1.0
1,3-butylene glycol ... 5.0
Zinc gluconate ... 0.1
Potassium hydroxide 0.3
Perfume ... proper amount antioxidant ... proper amount purified water ... balance

<Prescription Example 3> Emulsion (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether ... 0.1
N-coconut oil fatty acid acyl L-alkenyl ethyl-DL-chlorocarbonate
Squalane ... 8.0
Petrolatum ... 2.0
Beeswax 0.5
Sorbitan sesquioleate ... 0.8
Polyoxyethylene oleyl ether (20E.0) ・ ・ ・ 1.2
Carboxyvinyl polymer ... 0.2
Potassium hydroxide ... 0.1
1.3-Butylene glycol ... 7.0
Perfume ... proper amount antioxidant ... proper amount purified water ... balance

<Prescription Example 4> Packing agent (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether 0.5
Vinyl acetate resin emulsion ... 15.0
Polyvinyl alcohol ... 10.0
Jojoba oil ... 3.0
Glycerin ... 5.0
Titanium oxide ... 8.0
Kaolin 7.0
Ethanol ... 5.0
Perfume ... proper amount antioxidant ... proper amount purified water ... balance

<Prescription Example 5> Ointment (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether 0.2
Tocopherol acetate ... 0.5
Octyl paradimethylaminobenzoate 4.0
Butylmethoxybenzoylmethane ... 4.0
Stearyl alcohol ... 18.0
Owl ... 20.0
Glycerin monostearate ... 0.3
Vaseline 33.0
Perfume ... proper amount antioxidant ... proper amount purified water ... balance

<Prescription Example 6> Eyeshadow (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether 0.2
Bisabolol ... 0.2
Liquid paraffin 6.0
Methyl polysiloxane ... 2.0
Sorbitan sesquioleate ... 2.0
Talc ... Remaining mica ... 15.0
Sericite ... 5.0
Pigment ... 14.5
Pearl pigment ... 10.0
Perfume ... proper amount antioxidant ... proper amount

<Prescription Example 7> Drink (mass%)
α-mono p-hydroxyphenylethyl glyceryl ether 0.2
Taurine ... 3.0
Pyridoxine hydrochloride: 0.02
Thiamine sulfide ... 0.01
Riboflavin ・ ・ ・ 0.003
Anhydrous caffeine ... 0.05
Purified white sugar ... 5.0
D-sorbitol solution ... 2.0
Citric acid anhydride ... 0.2
Perfume ... appropriate amount purified water ... the balance

Jelly with fruit juice (% by mass)
α-mono p-hydroxyphenylethyl glyceryl ether ... 0.1
Grape juice ... 6.0
Minamata ... 3.5
Granulated sugar ... 13.0
Malic acid 0.2
Gelling agent ... 1.0
Sodium citrate 0.05
Caramel color ... 0.1
Fragrance 0.2
Purified water ... balance

The cosmetics prepared in the above-mentioned Formulation Example 1 were used for 20 weeks by 20 healthy female panelists for each cosmetic, and the use feeling and skin irritation were confirmed. As a result, no skin irritation was seen by one person, and an answer that fully satisfied the feeling of use was obtained.

The present invention relates to an antibacterial agent, and more specifically, α-mono p-hydroxyphenylethyl glyceryl ether having an antibacterial property equivalent to or better than that of paraoxybenzoic acid ester, and cosmetics, pharmaceuticals, quasi drugs, About food

Claims (5)

The following general formula (1)
The antibacterial agent which consists of (alpha) -mono p-hydroxyphenyl ethyl glyceryl ether represented by these. The skin external preparation characterized by mix | blending the alpha-mono p-hydroxyphenyl ethyl glyceryl ether shown by Claim 1. The pharmaceutical which mix | blends alpha-mono p-hydroxyphenyl ethyl glyceryl ether shown by Claim 1 . A quasi drug comprising the α-mono p-hydroxyphenylethyl glyceryl ether shown in claim 1. The foodstuff characterized by mix | blending the alpha-mono p-hydroxyphenyl ethyl glyceryl ether shown by Claim 1.