JP6907348B2 - Acne biofilm disruption composition - Google Patents

Description

The present invention relates to a P. acnes biofilm-destroying composition, and more particularly to an P. acnes biofilm-disrupting composition that inhibits the growth of P. acnes and radically improves acne.

Acne is a skin disorder that causes comedones, papules, nodules, and pustules that can be accompanied by inflammation of the hair follicles, mainly on the face, chest, and back. It is known that the main causative bacterium of acne is P. acnes, which is an indigenous bacterium of the skin.

P. acnes, an anaerobic bacterium, lives deep in the hair follicles and proliferates using the sebum accumulated in the hair follicles as nutrients, causing inflammation, and the inflammation causes pus to accumulate in the hair follicles, resulting in eczema. .. In order to treat such a symptom, various external preparations, oral preparations and the like have been developed for the purpose of suppressing sebum production, preventing infection, suppressing inflammation, normalizing keratinization and the like.

By the way, some bacteria form an accumulation of bacterial secretions (polysaccharides, etc.) called a biofilm and adhere to the adherend with viscosity. For example, sink slime is known to be a biofilm formed by bacteria. In addition, plaque that occurs between teeth and at the boundary between teeth and gums is considered to be a type of biofilm.

P. acnes is also known to form biofilms. Since polysaccharides and the like secreted from P. acnes are accumulated in the biofilm, it is difficult for agents such as antibacterial agents to penetrate into the biofilm, and the bactericidal effect is diminished. Therefore, since the presence or absence of biofilm formation affects the pathogenicity of various bacterial infections (Non-Patent Document 1), the development of antibacterial agents highly effective against biofilms is underway, and Staphylococcus aureus , Mutans bacteria, Escherichia coli and the like are already disclosed (Patent Document 1).
Further, the amino sugar derivative is known as a therapeutic agent for bifilm infection, which exhibits intractable infection by removing or destroying Pseudomonas aeruginosa biofilm (Patent Document 2).

Japanese Patent No. 3717960 Japanese Patent No. 3769040

Tom Coenye et al., Infectious Disorders-Drug Targets, 2008, 8, P.156-159

However, for P. acnes, which forms a biofilm deep in the hair follicle, the development of a formulation that destroys the biofilm has not yet been sufficiently carried out. Therefore, an object of the present invention is to provide a preparation having a high effect of destroying such a biofilm.

To achieve the above object, the present invention is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfadiazine and salts thereof, ethanol, resorcin, sulfur, and benzoyl peroxide. The first gist is a biofilm-destroying composition containing a species of P. acnes biofilm-destroying component (A).

Further, the present invention states that the P. acnes biofilm-destroying component (A) is at least one selected from the group consisting of isopropylmethylphenol, sulfadiazine and salts thereof, ethanol, resorcin, and benzoyl peroxide. This is the second gist. Further, in addition to the component (A), the third gist is that it contains at least one destructive auxiliary component (B) selected from the group consisting of chlorobutanol, propyl gallate, sodium lactate, and orange oil. ..

The acne biofilm-destroying component (A) is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfaziazine and salts thereof, resorcin, sulfur, and benzoyl peroxide. The fourth gist is that the content of the component (A) is 0.05 to 8% by weight based on the total amount of the P. acnes biofilm-destroying composition. The fifth gist is that it is ethanol and the content of the ethanol is 2.5 to 50% by weight based on the total amount of the P. acnes biofilm-destroying composition.
The sixth gist is that it is the P. acnes biofilm-destroying composition of the first to fifth gist, which is applied to the skin.

That is, as a result of repeated studies on biofilms formed by acne bacteria, the present inventors have confirmed components that have a bactericidal effect on acne bacteria but do not have an acne bacteria biofilm-destroying effect. , And found a biofilm-destroying composition having an acne bacterium biofilm-destroying effect, and found that using this biofilm-destroying composition can destroy the acne bacterium biofilm and radically improve acne, and reached the present invention. ..

That is, the biofilm-destroying composition of the present invention is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfadiazine and salts thereof, ethanol, resorcin, sulfur, and benzoyl peroxide. Since it contains a seed biofilm-destroying component (A), it has an excellent effect on biofilm-destroying P. acnes.

Further, the P. acnes biofilm-destroying component (A) in the biofilm-destroying composition is at least one selected from the group consisting of isopropylmethylphenol, sulfaziazine and salts thereof, ethanol, resorcin, and benzoyl peroxide. If there is, it has a so-called bactericidal effect, but also has a biofilm-destroying effect of P. acnes, which is different from the bactericidal effect.

In addition to the component (A), the Acne bacterium biofilm destruction composition further contains at least one destruction auxiliary component (B) selected from the group consisting of chlorobutanol, propyl gallate, sodium lactate, and orange oil. If so, the biofilm-destroying effect of the acne bacterium is further improved, and even if the content of the biofilm-destroying component (A) is low, a sufficient biofilm-destroying effect can be observed.

The acne biofilm-destroying component (A) is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfadiazine and salts thereof, resorcin, sulfur, and benzoyl peroxide. In some cases, from the viewpoint of the biofilm-destroying effect, the content thereof is preferably 0.05 to 8% by weight based on the total biofilm-destroying composition of Acne bacteria.

When the acne bacterium biofilm-destroying component (A) is ethanol, the content of the ethanol is 2.5 to 50% by weight of the entire acne bacterium biofilm-destroying composition from the viewpoint of the biofilm-destroying effect. Is preferable.

The P. acnes biofilm-disrupting composition is preferably applied to the skin.

FIG. 1A is a graph showing the results of the biofilm residual rate of the Acne bacterium biofilm destruction test of Example 1 product and Comparative Example 1 product, and FIG. 1B is a graph of Example 1 product and Comparative Example 1 product. It is a graph which shows the result of the bacterial viability rate of. FIG. 2 (a) shows an optical micrograph of Reference Example 1 (formation of acne bacterium biofilm in control), and FIG. 2 (b) shows an optical micrograph of Example 1. FIG. 3 is a graph showing the results of the acne bacterium biofilm destruction test of Examples 2 to 9 and Comparative Example 2. FIG. 4 is a graph showing the results of the acne bacterium biofilm destruction test in the change in isopropylmethylphenol concentration of the products of Examples 1-1 to 1-4. FIG. 5 is a graph showing the results of the acne bacterium biofilm destruction test in the change in ethanol concentration of the products of Examples 2-1 to 2-5. FIG. 6 is a graph showing the results of the acne bacterium biofilm destruction test in the resorcinol concentration change of the products of Examples 3-1 to 3-5. FIG. 7 is a graph showing the results of the Acne biofilm destruction test of Examples 10 to 13 containing the Acne biofilm destruction component (A) and the destruction auxiliary component (B). FIG. 8 is a graph showing the results of the Acne biofilm destruction test of Examples 14 to 16 containing the Acne biofilm destruction component (A) and the destruction auxiliary component (B).

Next, embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

The P. acnes biofilm-disrupting composition of the present invention is at least one selected from the group consisting of isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfaziazine and salts thereof, ethanol, resorcin, sulfur, and benzoyl peroxide. Contains the species P. acnes biofilm-destroying component (A). Here, P. acnes biofilm destruction means reducing the biofilm formed by microorganisms (P. acnes). The decrease in the biofilm is detected by a known method, but it is desirable that the residual rate of the biofilm is reduced to 80% or less, and further 60% or less, if the method described in the test example described later is used. In particular, 50% or less, particularly 40% or less is preferable. Hereinafter, the destruction of acne biofilm may be abbreviated as "BF destruction".

Hereinafter, the BF-destroying component (A), which is an essential component of the BF-destroying composition, will be described in detail.

<BF destruction component (A)>
The BF-destroying component (A) refers to isopropylmethylphenol, salicylic acid, glycyrrhizic acid, ibuprofen piconol, sulfaziazine and salts thereof, ethanol, resorcin, sulfur, and benzoyl peroxide, and above all, isopropyl from the viewpoint of BF-destroying effect. Methylphenol and salts thereof, ethanol and resorcin are preferable, and isopropylmethylphenol and salts thereof are preferable.
These BF-destroying components (A) can be used alone or in combination of two or more.

(I) Among the components (A), isopropylmethylphenol, sulfadiazine and salts thereof, ethanol, resorcin, and benzoyl peroxide have been conventionally known as bactericidal components, and not only have a bactericidal effect but also sterilize. It is preferably used because it has a biofilm-destroying effect different from that of.

(II) Furthermore, among the components (A), salicylic acid and its salts and sulfur have been conventionally known as keratin softening components, and have a keratin softening effect different from the biofilm-destroying effect together with the biofilm-destroying effect. Therefore, it is preferably used.

Among the components (III) and (A), glycyrrhizic acid, ibuprofen piconol and salts thereof have been conventionally known as anti-inflammatory components, and are preferable because they have an anti-inflammatory effect and a biofilm-destroying effect. Used.

In addition, various positional isomers are known for the isopropylmethylphenol component (A), and any of them may be used in the present invention. Specifically, the positional isomers of isopropylmethylphenol include 3-methyl-4-isopropylphenol [also called biozol], 2-isopropyl-5-methylphenol [also called thymol], or 2-methyl-5-isopropyl. Examples include, but are not limited to, phenol [also called carvacrol]. From the viewpoint of exhibiting the effect of the present invention, 3-methyl-4-isopropylphenol is preferable.

The salt of isopropylmethylphenol as the component (A) may be a pharmacologically acceptable salt, for example, a salt of a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, or an organic salt such as maleic acid or methanesulfonic acid. Examples thereof include acid salts, alkali metal salts such as sodium and potassium, and alkaline earth metal salts.

The salt of salicylic acid of the component (A) may be any pharmaceutically acceptable salt, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth such as a calcium salt or a magnesium salt. Metal salts; zinc salts; iron salts; ammonium salts; salts with basic amino acids such as arginine, lysine, histidine, ornithine; salts with amines such as monoethanolamine, diethanolamine, triethanolamine and the like.

Further, the salt of the glycyrrhizinic acid component (A) may be any pharmacologically acceptable salt, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkali such as a calcium salt or a magnesium salt. Earth metal salts; salt with amines such as tylamine, triethylamine, triethanolamine, morpholin, piperazine, pyrrolidine, tripyridine, picolin and the like can be mentioned. Among these, an alkali metal salt of glycyrrhizic acid and dipotassium glycyrrhizinate are preferable from the viewpoint of exhibiting the effect of the present invention.

The salt of ibuprofenpiconol as the component (A) may be a pharmacologically acceptable salt, for example, a salt of a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, maleic acid, methanesulfonic acid or the like. Examples thereof include salts of organic acids, alkali metal salts such as sodium and potassium, and alkaline earth metal salts.

The salt of sulfaziazine of the component (A) may be a pharmacologically acceptable salt, for example, a salt of a mineral acid such as sulfuric acid, hydrochloric acid or phosphoric acid, or an organic salt such as maleic acid or methanesulfonic acid. Examples include acid salts, metal salts such as sodium, potassium and silver.

[(A) Ingredient content]
(I) Of the BF breaking components (A), the content of the poorly water-soluble component and the water-soluble solid component is preferably 0.05 to 8% by weight of the entire BF breaking composition from the viewpoint of effect. .. Among the BF-destroying components (A), examples of the poorly water-soluble component include isopropylmethylphenol, salicylic acid, ibuprofen piconol, sulfadiazine and salts thereof, resorcin, sulfur, and benzoyl peroxide, and examples of the water-soluble solid component include benzoyl peroxide. Examples include glycyrrhizic acid and salts thereof. These can be used alone or in combination of two or more.

Above all, the content of at least one of isopropylmethylphenol and a salt thereof is preferably 0.05 to 1.5% by weight, particularly preferably 0.3 to 1% by weight, based on the total amount of the BF breaking composition. .. If it is within these ranges, an excellent biofilm-destroying effect is exhibited, while if it is less than 0.05% by weight, the biofilm-destroying effect tends to be relatively low, and if it exceeds 1.5% by weight, the odor intensity of the preparation is observed. There is a tendency that it is not suitable for practical use.

Further, the content of resorcin is particularly preferably 0.5 to 4% by weight based on the total amount of the BF breaking composition. If it is within this range, an excellent biofilm-destroying effect is exhibited, but if it is less than 0.5% by weight, the biofilm-destroying effect tends to be insufficient, and if it exceeds 4% by weight, the formulation is colored and is practically used. There is a tendency that it is not suitable for sex.

(II) Of the above-mentioned BF-destroying component (A), the content of the water-soluble liquid component is preferably 2.5 to 50% by weight of the entire BF-destroying composition from the viewpoint of effect, and particularly 2.5. ~ 30% by weight is preferable. Within these ranges, an excellent biofilm-destroying effect is exhibited, while when it is less than 2.5% by weight, the biofilm-destroying effect tends to be insufficient, and when it exceeds 30% by weight, the odor intensity is high and practical. There is a tendency that it is not suitable for sex. Among the BF-destroying components (A), ethanol is an example of a water-soluble liquid component.

<Destruction auxiliary component (B)>
Next, the biofilm breaking composition of the present invention preferably contains not only the above-mentioned component (A) but also a breaking auxiliary component (B). Here, the destruction auxiliary component means a component for assisting the destruction of the acne bacterium biofilm.

Examples of the destruction auxiliary component (B) include chlorobutanol, propyl gallate, sodium lactate, and orange oil, and among them, chlorobutanol, propyl gallate, and sodium lactate are more preferable. These destructive auxiliary components (B) can be used alone or in combination of two or more.

Chlorobutanol is used as a preservative, propyl gallate is used as an antioxidant for foods, sodium lactate is used as a moisturizing ingredient, and orange oil is used as an additive that is added to foods and beverages, perfume, detergents, etc. It has been used so far. The destruction auxiliary component (B) is a component completely different from the BF destruction component (A) in this way, but when used in combination with the component (A), the biofilm destruction effect can be effectively reinforced. .. Further, since the reinforcing effect is high, the biofilm-destroying effect can be sufficiently obtained even when the content of the component (A) is low and tends to be insufficient.

The content of the destruction auxiliary component (B) is preferably 0.001 to 10% by weight, more preferably 0.01 to 5% by weight, from the viewpoint of effectiveness and practicality, based on the total amount of the BF destruction composition. preferable.

<Other ingredients>
In addition, depending on various purposes, moisturizing ingredients, polyhydric alcohols, scrubbing agents, ultraviolet absorbing components, ultraviolet scattering components, anti-inflammatory agents other than component (A), astringent components, vitamins, peptides or derivatives thereof, amino acids or The derivative, the cleaning component, the bactericidal component other than the component (A), the keratin softening component, the cell activating component, the anti-aging component, the blood circulation promoting action component, the whitening component and other other components are within the range that does not impair the effect of the present invention. May be included in. Among them, it is preferable to contain polyhydric alcohols, vitamins, and anti-inflammatory agents other than the component (A). In addition, these other components may be used individually by 1 type, and may use 2 or more types together.

Examples of the moisturizing component include diglycerin trehalose; high molecular compounds such as sodium hyaluronate, heparinoid, chondroitin sodium sulfate, collagen, elastin, keratin, chitin, and chitosan; amino acids such as glycine, aspartic acid, and arginine; urea. , Natural moisturizing factors such as sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol and phospholipids; plant extracts such as chamomile extract, hamamelis extract, cha extract and perilla extract.

The polyhydric alcohol preferably has 2 to 10 carbon atoms, and for example, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, 1 , 3-butylene glycol, sorbitol, xylitol, erythritol, mannitol, pentandiol, hexanediol, octanediol, decanediol, neopentyl glycol and the like.

Among these, glycerin, diglycerin, triglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, ethylene glycol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, hexanediol, octanediol Is preferable, and glycerin, diglycerin, propylene glycol, dipropylene glycol, 1,3-butanediol, diethylene glycol, isoprene glycol, sorbitol, xylitol, erythritol, mannitol, pentanediol, and hexanediol are more preferable.

Examples of the scrubbing agent include apricot kernel powder, almond shell powder, apricot kernel powder, sodium chloride granules, olive kernel powder, seawater dried product granules, candelilla wax, walnut shell powder, cherry kernel powder, coral powder, and charcoal powder. , Sheath husk powder, polyethylene powder, silicic anhydride and the like.

Examples of the ultraviolet absorbing component include octylriazone, octyl dimethoxybenzylidene dioxoimidazolidine propionate, 2-ethylhexyl paramethoxycinnamate, and phenylbenzimidazole sulfonic acid.

Examples of the ultraviolet scattering component include inorganic compounds such as hydrous silicic acid, zinc silicate, cerium silicate, titanium silicate, zirconium oxide, cerium oxide, titanium oxide, iron oxide, and silicic anhydride, and these inorganic compounds. It is coated with inorganic powder such as hydrous silicic acid, aluminum hydroxide, mica or talc, compounded with resin powder such as polyamide, polyethylene, polyester, polystyrene or nylon, and further with silicone oil or fatty acid aluminum salt. Examples include processed ones.

Examples of anti-inflammatory agents other than the above component (A) include allantoin and its derivatives, glycyrrhetinic acid and its derivatives, azulene and its derivatives, components derived from plants (for example, comfrey), zinc oxide, tocopherol acetate, aminocaproic acid, and the like. Examples thereof include hydrocortisone, prednisolone and salts thereof. Among them, allantoin and its derivatives, glycyrrhetinic acid and its derivatives, azulene and its derivatives, and aminocaproic acid are preferable, and allantoin, allantoinchlorohydroxyaluminum, allantoindihydroxyaluminum, glycyrrhetinic acid, stearyl glycyrrhetinate, epsilonaminocaproic acid, azulene, guaiazulene and Those salts are more preferred, and allantoin is particularly preferred. The "derivative" refers to an ester, an ether, an alkylated product, a glycoside, or the like of the described compound.

Examples of the astringent component include zinc sulfate, zinc oxide, aluminum chloride, zinc sulfophenol, tannic acid and the like.

Examples of the vitamins include vitamin Es such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate; riboflavin, flavin mononucleotide, flavin. Vitamin B2s such as adenin dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinic acid ester; nicotinic acid, dl-α-tocopherol nicotinate, benzyl nicotinate, nicotinic acid Nicotinic acids such as methyl, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate, nicotinic acid amide; ascorbigen-A, ascorbic acid stearate, ascorbic acid palmitate, dipalmitate L- Vitamin Cs such as ascorbyl; Vitamin Ds such as methylhesperidine, ergocalciferol, cholecalciferol; Vitamin Ks such as phylloquinone and farnoquinone; γ-orizanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, Thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate, thiamine diphosphate, Vitamin B1s such as thiamine diphosphate ester hydrochloride, thiamine triphosphate ester, thiamine triphosphate monophosphate; pyridoxin hydrochloride, pyridoxin acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, vitamin B6 such as pyridoxamine hydrochloride; cyanocobalamine , Hydroxocobalamine, Vitamin B12 such as deoxyadenosylcobalamine; Folic acids such as folic acid and pteroylglutamic acid; Pantothenic acid, calcium pantothenate, pantothenyl alcohol (pantenol), D-pantesin, D-pantetin, coenzyme A, pantothenic acids such as pantothenyl ethyl ether; biotins such as biotin and biocytin; ascorbic acid derivatives such as ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbic acid phosphate, magnesium ascorbic acid phosphate. Vitamin Cs; carnitine, ferulic acid, α-lipoic acid, olo Examples include vitamin-like acting factors such as tacid.

Examples of the peptide or a derivative thereof include keratin-degrading peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-degrading peptide, collagen-degrading peptide, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, and the like. Elastin-degrading peptide, conchiolin-degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, Examples thereof include casein-degrading peptides and acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

Examples of the amino acid or a derivative thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, aspartic acid, aspartic acid, cysteine, and the like. Examples thereof include cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosin, creatine and the like.

Examples of the cleaning component include soaps selected from alkali metal salts such as potassium laurate, potassium myristate, potassium palmitate or potassium stearate, alkanolamide salts or amino acid salts; sodium cocoyl glutamate, sodium cocoyl methyl taurine. Amino acid-based surfactants such as; ether sulfate ester salts such as laureth sulfate Na; ether carboxylates such as lauryl ether acetate Na; sulfosuccinic acid ester salts such as alkyl sulfosuccinate Na; coconut oil fatty acid monoethanolamide, coconut oil Amino acid alkanolamides such as fatty acid diethanolamide; monoalkyl phosphates such as sodium lauryl phosphate and sodium polyoxyethylene lauryl ether phosphate; coconut oil fatty acid amide propyldimethylaminoacetic acid betaine, lauryldimethylaminoacetic acid betaine, 2-alkyl Betain-type amphoteric surfactants such as -N-carboxymethyl-N-hydroxyethyl imidazolinium betaine, lauryl hydroxysulfobetaine and lauroylamide ethyl hydroxyethyl carboxymethyl betaine hydroxypropyl phosphate; amino acids such as sodium lauryl aminopropionate Examples include type amphoteric surfactants.

Examples of the bactericidal component other than the above component (A) include chlorhexidine, benzalkonium chloride, acrinol, benzethonium chloride, cresol, gluconic acid and its derivatives, povidone iodine, potassium iodide, iodine, triclocarban, triclosan, and photosensitizer 101. No., Photosensitizer No. 201, Paraben, Phenoxyethanol, 1,2-Pentanediol, Alkyldiaminoglycine hydrochloride, Pyroctolamine, Myconazole and the like.

Examples of the keratin softening component include lactic acid, gluconic acid, citric acid, malic acid, fruit acid, phytic acid, urea, and sulfur.

Examples of the cell activating component include amino acids such as γ-aminobutyric acid and ε-aminocaproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride and pantothenic acid; α-hydroxy acids such as glycolic acid and lactic acid. ; Tannin, flavonoid, saponin, Photosensitizer No. 301 and the like can be mentioned.

Examples of the anti-aging component include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

Examples of the blood circulation promoting component include plants (for example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Uikyo, Enmeisou, Dutch oak, Chamomile, Roman chamomile, Carrot, Gentiana, Gobo, Rice, Sanzashi, Shiitake, Ginger, Seiyosanzashi, Seiyounezu. , Senkyu, Senburi, Thyme, Chouji, Chinpi, Togarashi, Touki, Tounin, Tohi, Carrot, Garlic, Butcher Bloom, Grape, Button, Maronie, Melissa, Yuzu, Yokuinin, Ryokucha, Rosemary, Rosehip, Peach, Annes, Ingredients derived from walnuts, corn, etc.); acetylcholine, ictamol, cantalistinki, gamma oryzanol, cepharanthin, trazoline, tocopherol nicotinate, glucosyl hesperidin and the like.

Examples of the whitening ingredient include tocopherol, tranexamic acid and the like.

<Manufacturing method of BF fracture composition>
The method for producing the BF-destroying composition of the present invention is not particularly limited, and is necessary for producing a normal pharmaceutical composition or the like in addition to the essential component (A) and, if necessary, the component (B). Various components (the above other components, bases or carriers described later, additives, etc.) can be appropriately selected and blended, and can be produced by a conventional method.

The BF breaking composition of the present invention may be an emulsified composition or a solubilized composition. In that case, either the oil-in-water type or the water-in-oil type may be used, but the oil-in-water type composition is used from the viewpoint of exhibiting the effect of the present invention and the usability (stickiness, spread, moist feeling, etc.) of the BF breaking composition. Is preferable.

<Use of BF fracture composition>
As described above, the BF-destroying composition of the present invention contains the BF-destroying component (A), so that it destroys the P. acnes biofilm and is used as a particularly effective pharmaceutical composition for the radical treatment of acne. It can be preferably used as an external preparation applied to the skin. The external preparation may be formulated by a known method in the form of a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment agent, a gel agent, a liniment agent, a lotion agent, an aerosol agent, a powder agent, a sheet agent or the like. can. It is preferably in the form of a liquid, a suspension, an emulsion or a cream, and more preferably in the form of a liquid, an emulsion or a cream.

The usage, dosage, etc. of the BF-destroying composition of the present invention are not particularly limited and vary depending on the age of the subject to be used, the degree of symptoms, etc., but are usually several times a day (for example, about twice a day in the morning and evening). ), Appropriate amount (for example, about 0.01 to 1 g) is applied (for example, application, spraying, application) to the outer skin such as skin (particularly, the affected part where symptoms are worrisome, for example, the part where acne occurs). Can be used. Specifically, it can be used for local administration of the skin surface such as face, lip circumference, scalp, neck, chest, back, abdomen, arms, oral cavity, axillary, buttocks, and pubic area. It can be administered topically for a variety of acne conditions, such as microacne (occurrence of keratin plugs, early clogging of keratin plugs), so-called pimples (adult acne), white acne (white follicles), black acne (open). It can be used as a prophylactic and / or therapeutic agent for acne) and inflamed red acne (red acne) or yellow acne (purulent acne). It is effectively used when P. acnes grows in or around hair follicles and forms a biofilm.

Dry skin, which is common in adult acne, is prone to excessive sebum secretion and clogging of keratin plugs, and such changes in the surrounding environment and stress may increase biofilm formation by P. acnes. In addition, when biofilm formation increases, there is concern that P. acnes protected by the biofilm is likely to repeatedly develop acne symptoms. It is known that an increase in biofilm formation causes an increase in lipase activity, and lipase decomposes triglyceride in sebum to produce free fatty acid, which causes inflammation in hair follicles. Therefore, the biofilm formation inhibitor of the present invention, more specifically, the BF-destroying composition of the present invention is used for the treatment or prevention of acne, and more specifically, the treatment of acne in dry skin. Alternatively, it can be used for prevention, for the treatment or prevention of acne that tends to repeat, or for the treatment or prevention of acne with inflammation in the hair follicles.

<Formulation>
In the BF breaking composition of the present invention, the essential components and other components described above are mixed according to a conventional method together with a base or carrier usually used for pharmaceutical products and, if necessary, additives described later. Then, it can be emulsified or solubilized as needed to obtain BF-disrupted compositions in various pharmaceutical forms.

Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, vaseline, gelled hydrocarbon (plastibase, etc.), ozokelite, α-olefin oligomer, light liquid paraffin, etc .; methylpolysiloxane, highly polymerized methylpolysiloxane. , Cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, Silicone oils such as polyglycerin-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone resins; fats and oils such as palm oil, olive oil, rice bran oil, and shea butter; waxes such as jojoba oil, beeswax, candelilla wax, and lanolin; , Cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol and other higher alcohols; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene Glycols; dioxane; polyester butylene glycol adipate; esters such as diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, pentaerythlit tetra-2-ethylhexanoate; Polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; lower alcohols such as ethanol and isopropanol; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, Diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, glycol ether such as dipropylene glycol monopropyl ether; water, etc. But Can be mentioned. When the BF breaking composition of the present invention contains a polyhydric alcohol, the polyhydric alcohol may also serve as a base or a carrier. Among them, the BF breaking composition of the present invention preferably contains water and / or a lower alcohol, and more preferably contains water.

When the BF breaking composition of the present invention contains a base or carrier other than water and lower alcohol, the base or carrier includes, for example, higher alcohol, hydrocarbon, fat, ester, silicone oil, brazing, vinyl. Higher alcohols are preferable, and higher alcohols, ester oils, silicone oils, and vinyl polymers are more preferable. Among these components, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, glyceryl tri-2-ethylhexanoate, dimethicone, cyclomethicone, polyether-modified silicone, polyglycerin-modified silicone, and carboxyvinyl polymer are more preferable.

The base or carrier described above may be used alone or in combination of two or more. In addition, the amount used thereof is appropriately selected from a range known to those skilled in the art.

<Formation form>
The formulation form of the BF-destroying composition of the present invention is not particularly limited, and for example, an ointment, a liquid, a suspension, an emulsifier (milky lotion and cream), a gel, a liniment, a lotion, a poultice, an aerosol, and a solid. Examples include agents. Of these, liquid to semi-solid pharmaceutical forms are preferable, and they are particularly useful when applied to liquids, lotions, ointments, gels, and emulsifiers. These preparations can be produced according to a conventional method, for example, the method described in the 16th revised Japanese Pharmacopoeia general rules for preparations.

<Additives>
The BF-destroying composition of the present invention is provided with known additives to be added to pharmaceutical products, such as surfactants, stabilizers, antioxidants, colorants, and pearl luster, as long as the effects of the present invention are not impaired. Agents, dispersants, chelating agents, pH adjusting agents, cooling agents, preservatives, thickeners, irritation reducing agents and the like can be added. Above all, it is preferable to add a refreshing agent and a thickener. These additives may be used alone or in combination of two or more.

The surfactant may be any of nonionic surfactants, cationic surfactants, anionic surfactants, amphoteric surfactants and the like, and for example, sorbitan monoisostearate and sorbitan monolaurate. , Solbitan monopalmitate, sorbitan monostearate, penta-2-ethylhexylate diglycerol sorbitan, tetra-2-ethylhexylate diglycerol sorbitan and other sorbitan fatty acid esters; propylene glycol fatty acid esters such as propylene glycol monostearate; Hardened polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polyoxyethylene hydrogenated castor oil 80, etc. Oil derivatives; polyoxyethylene monolaurate (20) sorbitan (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene monooleate (20) sorbitan (polysorbate 80), isostearic acid Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan; polyoxyethylene monopalm oil fatty acid glyceryl; glycerin alkyl ether; alkyl glucoside; polyoxyalkylene alkyl ether such as polyoxyethylene cetyl ether; stearylamine, oleylamine Amins such as: polyoxyethylene / methylpolysiloxane copolymer, silicone-based surfactants such as laurylPEG-9 polydimethylsiloxyethyl dimethicone and PEG-9 polydimethylsiloxyethyl dimethicone. Of these, nonionic surfactants are preferred, and cured castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, and polyoxyalkylene alkyl ethers are more preferred.

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, erythorbic acid, L-cysteine hydrochloride and the like.

Examples of the colorant include inorganic pigments and natural pigments.

Examples of the pearl gloss imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinylpyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, organic acid and the like.

Examples of the chelating agent include EDTA / disodium salt, EDTA / calcium / disodium salt and the like.

Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citrate, sodium citrate, succinate, sodium succinate, etc.), and inorganic bases (potassium hydroxide, water). (Sodium citrate, etc.), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.) and the like. Of these, inorganic bases and / or organic bases are preferable, and potassium hydroxide and triethanolamine are more preferable.

Examples of the refreshing agent include terpenes such as menthol, camphor, borneol, geraniol, cineol, anethole, limonene, and eugenol (these may be d-form, l-form, or dl-form); eucalyptus oil, bergamot. Examples thereof include essential oils such as oil, peppermint oil, cool mint oil, spare mint oil, eugenol oil, camphor oil, kehi oil, rose oil, and terpene oil.

Examples of the preservative include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid. Examples thereof include benzyl, methyl paraoxybenzoate, and phenoxyethanol.

Examples of the thickener include vinyl thickeners such as polyvinyl alcohol, polyvinylpyrrolidone, and carboxyvinyl polymers, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and carboxyethyl cellulose. Cellulose thickeners, guar gum, pectin, pullulan, gelatin, locust bean gum, carrageenan, agar, xanthan gum, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, chondroitin sulfate. Examples thereof include sodium, hyaluronic acid, sodium hyaluronate, (hydroxyethyl acrylate / acryloyldimethyltaurine Na) copolymer, (acryloyldimethyltaurinammonium / vinylpyrrolidone) copolymer and the like. Of these, vinyl-based thickeners and cellulose-based thickeners are preferable, and carboxyvinyl polymers, polyvinyl alcohols, polyvinylpyrrolidones, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxy Ethyl cellulose is more preferred.

Examples of the irritation reducing agent include licorice extract, sodium alginate, gum arabic, polyvinylpyrrolidone and the like.

The BF destruction effect of the BF destruction composition of the present invention can be confirmed by measuring the biofilm residual ratio (hereinafter, may be abbreviated as "BF residual ratio") by the BF destruction test described later.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

<Test 1: BF destruction test>
The biofilm-destroying effect is confirmed by measuring the BF residual rate after adding the sample of the example product or the like to the medium in which P. acnes has formed a biofilm.
Specifically, 48 well round bottom well plates, 3 days 37 ° C. with reinforced clostridia (RCM) slant medium, Propionibacterium acnes (P. acnes) suspensions anaerobic cultures to 10 ⁹ (CFU / mL) bacterial suspension Dispense 500 μL of each test solution inoculated so as to be. The cells are anaerobically cultured at 37 ° C. for 28 hours to allow the bacteria to adhere to the wells and form a biofilm. Discard the bacterial solution and wash each well twice with 500 μL phosphate buffered saline (PBS).

Each sample is dispensed at 500 μL per well and then anaerobically cultured for 24 hours. After culturing, each well is washed twice with 500 μL PBS. Methanol (manufactured by Wako Pure Chemical Industries, Ltd.) is dispensed at a rate of 500 μL per well, allowed to stand for 15 minutes, then the methanol is removed and dried.

The cells were stained with 100 μL of 0.5 wt% crystal violet (manufactured by Kanto Chemical Co., Inc.) per well for 20 minutes. The crystal violet solution is removed, each well is washed twice with 500 μL of purified water, and then 150 μL of 33 wt% acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.) is used to dissolve the attached crystal violet and shaker (Shaking Incubator SI-). Shake at 300 rpm for 5 minutes using 300 (manufactured by AS ONE Corporation). The extract of each well was dispensed into a 96-well flat plate at a rate of 100 μL per well, and the absorbance at 590 nm, which is the absorbance of crystal violet, was measured using a microplate reader (Versa max, manufactured by Molecular Devices). The sample OD ₅₉₀ value is used.

An RCM medium containing 2.5% by weight dimethyl sulfoxide (DMSO, manufactured by Wako Pure Chemical Industries, Ltd.) was prepared as a control, and the biofilm remained by the following formula (1) using the ratio to the biofilm formation amount. Calculate the rate.

Equation (1): Biofilm residual rate (%) = sample OD ₅₉₀ value / control OD ₅₉₀ value x 100

The Dunnett test was used to calculate the P-value for the statistically significant difference test. The experiment is carried out with an n number of 6.

<Test 2: Bacterial survival rate measurement>
Bacterial viability is measured using the Cell Titer-Blue Cell Viability Assay kit (manufactured by Promega).
Each Specifically was inoculated to a 48 well round bottom well plates for 3 days 37 ° C. in RCM slant medium, Propionibacterium acnes (P. acnes) was anaerobically cultured suspension 10 ⁹ (CFU / mL) bacterial suspension Dispense 500 μL of test solution per well. The cells are anaerobically cultured at 37 ° C. for 28 hours to allow the bacteria to adhere to the wells and form a biofilm. Discard the bacterial solution and wash each well twice with 500 μL PBS.

Each sample is dispensed at 500 μL per well and then anaerobically cultured for 24 hours. Each well is washed twice with 500 μL PBS. After dispensing 500 μL physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) and 100 μL Cell Titer blue (manufactured by Promega) into each well and anaerobically culturing at 37 ° C. for 1 hour, a fluorescent microplate reader (manufactured by Molecular Device Co., Ltd., Flex station) ) Is used for fluorescence measurement (Ex: 560 nm, Em: 590 nm).

An RCM medium containing 2.5% by weight DMSO (manufactured by Wako Pure Chemical Industries, Ltd.) is prepared as a control, and the bacterial survival rate is calculated by the following formula (2) using the ratio to the fluorescence value.

Equation (2): Bacterial viability (%) = sample fluorescence value / control fluorescence value x 100

The Dunnett test was used to calculate the P-value for the statistically significant difference test. The experiment is carried out with an n number of 6.

First, prior to the examples, Reference Example 1 (control) shown below was prepared, and Examples / Comparative Examples containing the component (A) and, if necessary, the component (B) were prepared.

[Reference Example 1]
As a control, 2.5 wt% DMSO was prepared.

[Example 1, Comparative Example 1]
A BF breaking composition blended with the control of Reference Example 1 so as to have the content of the component (A) in Table 1 below is prepared.

The above-mentioned BF destruction test and bacterial survival rate measurement were performed on the above-mentioned Reference Example 1 product, Example 1 product, and Comparative Example 1 product. The results of these BF destruction tests are shown in Table 1 above and shown in FIG. 1 (a), and the results of bacterial viability measurement are shown in FIG. 1 (b).

As a result of measuring the bacterial viability, from FIG. 1 (b), the bacterial viability of Example 1 and Comparative Example 1 which have been conventionally known as bactericidal components is almost 0%, and these bactericidal effects are exhibited. confirmed.

On the other hand, as a result of the BF destruction test, it was found from Table 1 and FIG. 1 (a) that the BF residual rate of the product of Example 1 was reduced to 29% and the BF destruction was effectively performed. On the other hand, the product of Comparative Example 1 containing azelaic acid known as a P. acnes fungicide had a BF residual rate of 89%, and was found to have almost no BF-destroying effect. As described above, some P. acnes fungicides are not the BF-destroying component (A), and as a result of diligent studies, the present inventors have made a number of components for the radical treatment of acne. It can be seen that the BF-destroying component (A) capable of BF-destroying has been found.

<Test 3: Observation of BF destruction state>
The results of Reference Example 1 (Control) and Example 1 after dyeing the biofilm with crystal violet used in the BF destruction test of Test 1 above were measured with an optical microscope (manufactured by Carl Zeiss) at a magnification of 50 times. Observing under the conditions of (eyepiece x 10, objective lens x 5), the optical micrograph of Reference Example 1 is shown in FIG. 2 (a), and the optical micrograph of Example 1 is shown in FIG. 2 (b). rice field.

As a result, as can be seen from FIG. 2, the biofilm dyed with crystal violet was widely present in the product of Reference Example 1, whereas the amount of dyed crystal violet was significantly reduced in the product of Example 1. It turned out that the biofilm had been destroyed.

[Examples 2 to 9, Comparative Example 2]
Next, each of the BF breaking compositions blended with the above control so as to have the content of the component (A) in Table 2 below was prepared.

The BF destruction test of Test 1 was carried out on the products of Examples 2 to 9 and Comparative Example 2. The results are shown in Table 2 and FIG. From Table 2 and FIG. 3, the product of Comparative Example 2 has a BF residual rate of 98% and the biofilm is hardly reduced, and is known as an acne active ingredient as in Comparative Example 1 above, but has a BF-destroying effect. Turned out to be none at all. On the other hand, it was found that all of the products of Examples 2 to 9 had a BF residual rate of less than 60% and exhibited a BF destructive effect.

Next, the BF-destroying effect on changes in the concentration of isopropylmethylphenol (IPMP), which is one of the BF-destroying components (A), was examined.

[Examples 1-1 to 1-4]
BF-disrupted compositions blended with the above controls so as to have the IPMP (A) content shown in Table 3 below were prepared.

The BF destruction test of Test 1 was carried out on the products of Examples 1-1 to 1-4. The results are shown in Table 3 and FIG. From Table 3 and FIG. 4, the products of Examples 1-1 to 1-4 had BF residual rates of 30%, 29%, 11%, and 10%, respectively, and exhibited a certain BF destruction effect. It turned out that there was.

In addition, the BF-destroying effect on changes in ethanol concentration, which is one of the BF-destroying components (A), was examined.

[Examples 2-1 to 2-5]
A BF breaking composition was prepared by blending the above controls with the ethanol (A) content shown in Table 4 below.

The BF destruction test of Test 1 was carried out on the products of Examples 2-1 to 2-5. The results are shown in Table 4 and FIG. From Table 4 and FIG. 5, it was found that all of the products of Examples 2-1 to 2-5 had a BF residual rate of less than 60% and exhibited a certain BF destruction effect.

Furthermore, the BF-destroying effect on the change in resorcin concentration, which is one of the BF-destroying components (A), was examined.

[Examples 3-1 to 3-5]
BF-disrupted compositions blended with the above controls so as to have the resorcin (A) content shown in Table 5 below were prepared.

The BF destruction test of Test 1 was carried out on the products of Examples 3-1 to 3-5. The results are shown in Table 5 and FIG. From Table 5 and FIG. 6, it was found that all of the products of Examples 3-1 to 3-5 showed a BF residual rate of 40% or less and exhibited a certain BF destruction effect.

The BF destruction effect when the BF destruction composition contains the BF destruction component (A) and the destruction auxiliary component (B) was examined.

[Examples 10 to 13]
A BF breaking composition was prepared by blending the above controls with the content of the component (A) and the content of the component (B) shown in Table 6 below.

The BF destruction test of Test 1 was carried out on the products of Examples 10 to 13. The results are shown in Table 6 and FIG. 7. From Table 6, FIG. 7 and FIG. 4, even a composition containing 0.025% by weight of a low concentration IPMP can exhibit an excellent BF destruction effect by using the above-mentioned destruction auxiliary component (B) in combination 0.1. It was found that a BF-destroying effect comparable to that of the composition containing% by weight of IPMP was exhibited.

[Examples 14 to 16]
A BF breaking composition was prepared by blending the above controls with the content of the component (A) and the content of the component (B) shown in Table 7 below.

The BF destruction test of Test 1 was carried out on the products of Examples 14 to 16. The results are shown in FIG. 8 together with Table 7 above. From Table 7, FIG. 8 and FIG. 6, even a composition containing a low concentration resorcin of 0.25% by weight, which tends to have an insufficient BF destruction effect, can be used in combination with the above-mentioned destruction auxiliary component (B). It was found that a BF-destroying effect similar to that of a 0.5% by weight resorcin-containing composition or the like exhibiting an excellent BF-destroying effect was exhibited.

(Example of formulation)
Hereinafter, Tables 8 and 9 below show examples of pharmaceutical formulations for the acne biofilm-destroying composition of the present invention.

Since the BF-destroying composition of the present invention can destroy a biofilm, it is very effective as an external composition for external medicines, quasi-drugs, cosmetics, etc., which is effective for the radical treatment of acne.

Claims (4)

Containing ibuprofen pico Knoll and at least one of P. acnes biofilm disruption component thereof selected from salts or Ranaru group (A), for the treatment or prevention of acne symptoms repeated due to biofilm formation P. acnes Composition for destroying P. acnes biofilm used in. Furthermore, chlorobutanol, propyl gallate, sodium lactate, and at least one breaking auxiliary component (B) according to claim 1 Symbol placement of P. acnes biofilm disruption compositions containing selected from the group consisting of orange oil. The content of the above SL component (A) is 0.05 to 8 wt% of the total P. acnes biofilm disruption composition, according to claim 1 or P. acnes biofilm disruption composition according to 2. The composition for destroying P. acnes biofilm according to any one of claims 1 to 3 , which is applied to the skin.

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