Inhibitor of expression of receptor for adherence of pneumonia-causing bacteria, oral composition, and composition

Abstract

To provide an inhibitor of expression of a receptor for adherence of pneumonia-causing bacteria.SOLUTION: An inhibitor of expression of a receptor for adherence of pneumonia-causing bacteria comprises at least one selected from the group consisting of hesperidin, cinnamaldehyde, citric acid hydrate, L-glutamic acid hydrochloride, and tartaric acid.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an inhibitor of pneumonia-causing bacteria adhesion receptor expression, an oral composition, and a composition. [Background technology]

[0002] Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, etc. are known to cause pneumonia. The onset of pneumonia caused by pneumonia-causing bacteria is triggered by the attachment of the bacteria to receptors such as PAFR (platelet-activating factor receptor) and ICAM-1 (intercellular adhesion molecule-1).

[0003] It has been reported that the onset of pneumonia can be induced by other viruses or pathogenic bacteria. For example, Non-Patent Document 1 describes a secondary infection of pneumonia-causing bacteria caused by influenza virus infection. For example, Non-Patent Document 2 describes that the expression of PAFR is promoted by the periodontal pathogen Porphyromonas gingivalis (Pg).

[0004] It is believed that the onset of pneumonia can be suppressed if the expression of receptors to which pneumonia-causing bacteria can adhere can be suppressed. Expression inhibitors that suppress the expression of cell adhesion factors are known, for example, as disclosed in Patent Document 1. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Application Publication No. 2018-100227 [Non-patent literature]

[0006] [Non-Patent Document 1] "Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness.", The Lancet infectious diseases, 2006, 6.5, p.303-312 [Non-patent document 2] "Porphyromonas gingivalis enhances pneumococcal adhesion to human alveolar epithelial cells by increasing expression of host platelet-activating factor receptor.", FEBS letters, 2021, 595.11, p.1604-1612 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need to inhibit the expression of pneumonia-causing bacterial adhesion receptors, which are involved in the onset of pneumonia. [Means for solving the problem]

[0008] Various aspects for solving the above problems will be described. The pneumonia causative bacteria adhesion receptor expression inhibitor of Aspect 1 contains at least one selected from the group consisting of hesperidin, cinnamaldehyde, citric acid hydrate, L-glutamic acid hydrochloride, and tartaric acid.

[0009] The oral composition of Aspect 2 contains the pneumonia-causing bacteria adhesion receptor expression inhibitor of Aspect 1. A composition according to embodiment 3 contains the pneumonia-causing bacteria adhesion receptor expression inhibitor according to embodiment 1, and is delivered by an inhaler. [Effects of the Invention]

[0010] According to the present invention, an excellent inhibitory effect on the expression of pneumonia-causing bacteria adhesion receptors can be exerted. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, the pneumonia pathogenic bacteria adhesion receptor expression inhibitor, oral composition, and specific embodiments of the composition will be described. Hereinafter, the pneumonia pathogenic bacteria adhesion receptor expression inhibitor will sometimes be abbreviated as "expression inhibitor."

[0012] The following mainly describes the inhibitor of pneumonia pathogenic bacteria adhesion receptor expression. The oral composition and composition contain the inhibitor of pneumonia pathogenic bacteria adhesion receptor expression described below. In this specification, oral composition refers to a composition intended primarily for use in the oral cavity. It includes not only oral preparations that are excreted from the oral cavity after use, but also ingestible foods and beverages. The inhibitor of pneumonia pathogenic bacteria adhesion receptor expression of this embodiment is not limited to those intended for use in the oral cavity.

[0013] <Ingredients> The pneumonia-causing bacteria adhesion receptor expression inhibitor contains at least one selected from the group consisting of hesperidin, cinnamaldehyde, citric acid hydrate, L-glutamic acid hydrochloride, and tartaric acid.

[0014] Hesperidin is a type of polyphenol that can be extracted from citrus peels, etc. Hesperidin may be extracted or chemically synthesized. Cinnamaldehyde is an aromatic aldehyde that can be extracted from cinnamon. Cinnamaldehyde can be extracted or chemically synthesized.

[0015] The expression inhibitor may contain only one of the above components, or may contain an appropriate combination of two or more of them. The content of the above-mentioned components in the expression inhibitor is not particularly limited, but is, for example, 0.0001% or more and 10% or less. The lower limit of the content of the above-mentioned components is preferably 0.001%, more preferably 0.01%. The upper limit of the content of the above-mentioned components is preferably 5%, more preferably 1%.

[0016] <Other ingredients> The pneumonia pathogenic bacteria adhesion receptor expression inhibitor, oral composition, and composition may contain other components in addition to the components described above, depending on the intended application, form, use, etc. Examples of other components include surfactants, flavoring agents, sweeteners, humectants, binders, preservatives, colorants, pH adjusters, chelating agents, medicinal ingredients, bases, abrasives, stabilizers, etc. Known components that are incorporated into expression inhibitors, oral compositions, and compositions can be used. The expression inhibitor, oral composition, and composition may contain only one of the above-mentioned other components alone, or may contain two or more of them in combination.

[0017] Examples of surfactants include nonionic surfactants, anionic surfactants, amphoteric surfactants, and cationic surfactants. Specific examples of nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; glycerin fatty acid esters; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers having a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group having 13 to 15 carbon atoms; polyoxyethylene alkyl phenyl ethers having a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group having 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; and fatty acid polyoxyethylene sorbitan (also known as polysorbate).

[0018] Specific examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and polyoxyethylene lauryl ether sodium sulfate; sulfosuccinate salts such as sodium lauryl sulfosuccinate and polyoxyethylene lauryl ether sodium sulfosuccinate; acylamino acid salts such as sodium lauroyl methyl alanine; and sodium cocoyl methyl taurate.

[0019] Specific examples of amphoteric surfactants include acetate betaine surfactants such as lauryl dimethylamino acetate betaine and coconut oil fatty acid amidopropyl dimethylamino acetate betaine; imidazoline surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium; and amino acid surfactants such as N-lauryl diaminoethylglycine.

[0020] Specific examples of cationic surfactants include distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, N-coconut oil fatty acid acyl-L-arginine ethyl-DL-pyrrolidone carboxylate, and the like.

[0021] Specific examples of flavoring agents include menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, fennel oil, cinnamon oil, anise oil, peppermint oil, and vanillin.

[0022] Specific examples of sweeteners include saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, and p-methoxycinnamic aldehyde.

[0023] Specific examples of the humectant include sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactite, polyoxyethylene glycol, and the like.

[0024] Specific examples of binders include cellulose derivatives such as sodium carboxymethylcellulose, carboxymethylethylcellulose salts, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, crystalline cellulose, and crystalline cellulose-carmellose sodium; microbially produced polymers such as xanthan gum; natural polymers or natural rubbers such as tragacanth gum, karaya gum, gum arabic, guar gum, carrageenan, dextrin, agar, pectin, pullulan, gellan gum, locust bean gum, and sodium alginate; synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl methyl ether, and sodium polyacrylate; thickening silica; inorganic binders such as Veegum; and cationic binders such as O-[2-hydroxy-3-(trimethylammonio)propyl]hydroxyethylcellulose chloride.

[0025] Specific examples of preservatives include parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, and alkyldiaminoethylglycine hydrochloride.

[0026] Specific examples of colorants include legally mandated dyes such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3; mineral dyes such as ultramarine, enhanced ultramarine, and Prussian blue; and titanium oxide. Specific examples of pH adjusters include citric acid, phosphoric acid, lactic acid, glycerophosphate, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, and the like.

[0027] Specific examples of the chelating agent include edetic acid, sodium edetate, potassium edetate, phytic acid, pyrophosphoric acid, polyphosphoric acid, malic acid, and the like. Specific examples of medicinal ingredients include vitamin E compounds such as dl-α-tocopherol acetate, tocopherol succinate, and tocopherol nicotinate; vitamin C compounds such as ascorbic acid, sodium ascorbate, and magnesium ascorbyl phosphate; vitamin B6 compounds such as pyridoxine hydrochloride; amphoteric disinfectants such as glycyrrhizinate and its derivatives, glycyrrhetinic acid, and dodecyldiaminoethylglycine; nonionic disinfectants such as triclosan, isopropylmethylphenol, and polyoxyethylene lauryl ether; anionic disinfectants such as sodium cocoyl sarcosinate and sorbic acid; cetylpyridinium chloride, chlorhexidine hydrochloride, and chlorhexidine gluconate. Examples of effective disinfectants include cationic disinfectants such as methacrylate, benzalkonium chloride, and benzethonium chloride; enzymes such as dextranase, amylase, protease, mutanase, lysozyme, and lytic enzyme (Retec Enzyme); alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate; fluorides such as sodium fluoride and stannous fluoride; tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, hinokitiol, copper chlorophyllin sodium, chlorophyll, sodium chloride, callopeptide, allantoin, carbazochrome, potassium nitrate, and palatinit.

[0028] Specific examples of the base include alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, and the like.

[0029] Specific examples of alcohols include ethyl alcohol, lauryl alcohol, and myristyl alcohol. Specific examples of abrasives include calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium phosphate, silica, zeolite, sodium metaphosphate, aluminum hydroxide, magnesium hydroxide, calcium pyrophosphate, red iron oxide, calcium sulfate, and silicic anhydride.

[0030] Specific examples of stabilizers include sodium thiosulfate, sodium sulfite, calcium lactate, lanolin, triacetin, castor oil, magnesium sulfate, and the like. <Applications, uses, and dosage forms> The application form of the pneumonia-causing bacteria adhesion receptor expression inhibitor, oral composition, and composition is not particularly limited, and they can be used, for example, as pharmaceuticals, quasi-drugs, or cosmetics.

[0031] The inhibitor of pneumonia causative bacteria adhesion receptor expression, the oral composition, and the composition can be used to inhibit the expression of pneumonia causative bacteria adhesion receptors. Specific uses include, for example, chewing agents, oral dissolving agents, oral disintegrating agents, tongue care agents, mouth fresheners, mouthwashes, gargles, dentifrices, agents for preventing bad breath, gum massage agents, oral moisturizing agents, tongue coating removers, oral application agents, oral disinfectants, throat disinfectants, oral throat agents, periodontal disease treatment agents, denture coating agents, denture stabilizers, denture preservatives, denture cleaners, implant care agents, inhalants, etc. Examples of dentifrices include toothpaste, powder dentifrice, liquid dentifrice, moisturizing dentifrice, etc.

[0032] The pneumonia-causing bacteria adhesion receptor expression inhibitor, oral composition, and composition contain a solvent, such as water, alcohol, etc. The dosage form of the expression inhibitor, oral composition, and composition is not particularly limited, and may be in the form (dosage form) of, for example, ointment, paste, spray, gel, liquid, suspension, powder, gum, tablet, drop, etc.

[0033] [Composition for inhaler] An example of a composition containing an inhibitor of pneumonia-causing bacteria adhesion receptor expression is a composition delivered by an inhaler.

[0034] One form of composition that can be delivered by an inhaler is a liquid or suspension. Such a composition can be dispersed into a mist and inhaled through the mouth or nose. Examples of inhalers that can be used include pressurized metered dose inhalers, soft mist metered dose inhalers, and nebulizers.

[0035] One form of composition that can be delivered by inhaler is a powder, which can be inhaled through the mouth or nose using, for example, a dry powder metered dose inhaler. <Actions and Effects of This Embodiment> The operation of this embodiment will be described.

[0036] The pneumonia pathogenic bacteria adhesion receptor expression inhibitor of this embodiment exhibits the effect of suppressing the expression of pneumonia pathogenic bacteria adhesion receptors. The pneumonia pathogenic bacteria adhesion receptor expression inhibitor of this embodiment can suitably suppress the expression of pneumonia pathogenic bacteria adhesion receptors in the presence of a factor that promotes the expression of pneumonia pathogenic bacteria adhesion receptors. Examples of pneumonia pathogenic bacteria adhesion receptors include ICAM-1 and PAFR. Examples of factors that promote the expression of pneumonia pathogenic bacteria adhesion receptors include Pg bacteria and influenza viruses.

[0037] The effects of this embodiment will be described. (1) The excellent inhibitory effect on the expression of pneumonia-causing bacteria adhesion receptors suppresses the expression of receptors to which pneumonia-causing bacteria can adhere. As a result, adhesion of pneumonia-causing bacteria is suppressed. This can be expected to have effects on preventing infection with pneumonia-causing bacteria, suppressing the onset of pneumonia, preventing pneumonia, and preventing the worsening of pneumonia. Because the above effects are achieved by suppressing the adhesion of pneumonia-causing bacteria, the increase of drug-resistant bacteria can be prevented, unlike when using disinfectants, antibiotics, etc.

[0038] (2) For example, P. g bacteria in the oral cavity may enter the trachea due to dysphagia. If the expression of the pneumonia-causing bacteria adhesion receptor is promoted by P. g bacteria, there is a risk of inducing the onset of pneumonia. Even in such cases, according to the pneumonia-causing bacteria adhesion receptor expression inhibitor, the expression of the pneumonia-causing bacteria adhesion receptor can be preferably suppressed. That is, even for aspiration pneumonia caused by dysphagia, an effect of suppressing its onset, a preventive effect, and a preventive effect on exacerbation can be expected.

[0039] (3) According to the composition that can be delivered by an inhaler, the pneumonia-causing bacteria adhesion receptor expression inhibitor can easily reach the trachea, bronchi, lungs, etc. Therefore, it can be expected that the pneumonia-causing bacteria adhesion receptor expression inhibitory action will be more preferably exerted.

[0040] <Modified Example> Note that the above embodiment can be implemented with the following modifications. The present embodiment and the following modified examples can be implemented in combination with each other within a technically non-conflicting range.

[0041] · It may be applied to pet animals other than humans, such as pets and livestock.

Example

[0042] The pneumonia-causing bacteria adhesion receptor expression inhibitor, the oral composition, and the composition will be further described in more detail based on the following examples. Note that the pneumonia-causing bacteria adhesion receptor expression inhibitor, the oral composition, and the composition are not limited to the configurations described in the example column.

[0043] <Medium> · Cell culture medium: DMEM medium supplemented with 10% FBS, 100 U / mL penicillin, and 100 μg / mL streptomycin · Bacterial culture medium: BHI medium supplemented with 5 μg / mL hemin and 0.4 μg / mL menadione <Preparation of P. g culture supernatant> Porphyromonas gingivalis (FDC381) was cultured for 3 days. The cultured bacterial solution was OD after blank correction 600The bacterial solution was centrifuged at 10,000×g at 4° C. for 20 minutes, and then filter-sterilized using a membrane filter with a pore size of 0.22 μm to obtain a Pg culture supernatant.

[0044] <Test example> A549 cells, which are cells derived from human alveolar epithelium, were seeded onto a 24-well plate and cultured to confluence. For the examples and comparative examples, 100 μL / mL of Pg culture supernatant and each of the materials listed in Table 1 were added to each well. The materials listed in Table 1 were diluted with bacterial medium to the concentrations listed in Table 1. As a positive control, 100 μL / mL of Pg culture supernatant and bacterial medium were added. As a negative control, bacterial medium was added. The plates were then cultured for 24 hours.

[0045] After culturing, the cells were harvested, RNA was isolated using standard methods, and the expression level of the receptor (ICAM-1) gene was measured by RT-qPCR. It was confirmed that the expression level in the positive control was more than six times higher than that in the negative control. After measuring the expression level, the receptor gene expression inhibition rate was calculated based on the following formula (1). The results are shown in Table 1. The higher the receptor gene expression inhibition rate, the more receptor expression can be expected to be inhibited.

[0046]

number

[0047] In formula (1), X sample represents the expression level in each Example and Comparative Example. pg(+) represents the expression level in the positive control. pg(-) indicates the expression level in the negative control.

[0048] [Table 1]

[0049] In all of Examples 1 to 5, the receptor gene expression inhibition rate was 30% or higher. It can be seen that in all Examples, receptor gene expression can be suitably inhibited in the presence of a factor that promotes receptor gene expression, such as the Pg culture supernatant in this test. It can also be seen that the excellent receptor gene expression inhibitory effect is exerted by including at least one selected from the group consisting of hesperidin, cinnamaldehyde, citric acid hydrate, L-glutamic acid hydrochloride, and tartaric acid.

Claims

1. An agent for suppressing the expression of pneumonia-causing bacteria adhesion receptors, comprising at least one member selected from the group consisting of hesperidin, cinnamaldehyde, citric acid hydrate, L-glutamic acid hydrochloride, and tartaric acid.

2. An oral composition comprising the pneumonia-causing bacteria adhesion receptor expression inhibitor according to claim 1.

3. A composition comprising the pneumonia-causing bacteria adhesion receptor expression inhibitor of claim 1, which is delivered by an inhaler.

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