Antibacterial agents

Abstract

To provide an antibacterial agent that does not exhibit antibacterial activity against Staphylococcus aureus in a resident state and exhibits selective antibacterial activity against target bacteria.SOLUTION: An antibacterial agent comprises a Chinese herbal extract selected from the group consisting of Shin'iseihaito, Keigai-rengryoto, Kakkonto-ka-senkyu-sini, and Shoseiryuto. Each of the extracts is used in a predetermined dose. The antibacterial agent does not exhibit antibacterial activity against Staphylococcus aureus in a resident state and exhibits selective antibacterial activity against target bacteria.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an antibacterial agent which does not exhibit antibacterial activity against resident Staphylococcus aureus, but exhibits selective antibacterial activity against target bacteria. [Background technology]

[0002] The human body is home to a population of symbiotic microorganisms known as resident bacteria (bacterial flora), which act as a defense against the invasion of pathogens from the outside. However, when the body's resistance is weakened due to illness or psychological stress, the appropriate balance of the bacterial flora is disrupted, leading to the overgrowth of some resident bacteria and the invasion and proliferation of other pathogens, which results in the development of various infectious disease symptoms.

[0003] Treatment of bacterial infections is generally carried out using antibacterial drugs that have the effect of inhibiting bacterial growth, bacteriostatic, or bactericidal. For example, various antibacterial drugs such as penicillin-based antibacterial drugs and antifungal drugs against mold and the like are used.

[0004] Here, Staphylococcus aureus, a gram-positive coccus, is known as a common bacterium frequently detected on human skin, nasal cavity, etc. Like other common bacteria, Staphylococcus aureus can cause inflammation due to abnormal proliferation, but in a typical adult, it usually subsides with mild purulent symptoms or food poisoning symptoms, and rarely causes serious infections.

[0005] On the other hand, it is known that in people with low resistance and physical strength, such as the elderly, hospitalized patients, and those suffering from illness, the abnormal proliferation of Staphylococcus aureus is likely to cause symptoms such as fever and diarrhea, as well as inflammation that can become severe, leading to severe infections such as pneumonia, septicemia, infective endocarditis, osteomyelitis, peritonitis, and meningitis. In such cases, further aggravation can be prevented or treated by using appropriate antibacterial agents against Staphylococcus aureus.

[0006] Here, Staphylococcus aureus has the property of easily acquiring resistance to antibacterial drugs. Therefore, even if the symptoms of an infection can be improved by administering an antibacterial drug, Staphylococcus aureus may take advantage of the exposure to an environment that is difficult for the antibacterial drug to grow in and acquire resistance. Once Staphylococcus aureus acquires such antibacterial drug resistance, if an infection occurs later due to abnormal proliferation, the antibacterial drug will no longer be effective, making treatment difficult.

[0007] A typical example of Staphylococcus aureus that has acquired resistance to antibiotics is methicillin-resistant Staphylococcus aureus. This resistant bacterium was discovered as Staphylococcus aureus that is resistant to methicillin, but in fact it is known to have acquired resistance to many antibiotics, not just methicillin. Methicillin-resistant Staphylococcus aureus is likely to appear in hospitals where antibiotics are frequently used, and is known to be the causative agent of mass infections.

[0008] On the other hand, some herbal medicines and Chinese medicines have been reported to have antibacterial properties. For example, it has been reported that Shini-seihai-to has a growth inhibitory effect against gram-positive bacteria, Streptococcus pneumoniae (Non-Patent Document 1). In addition, Shini-seihai-to has been confirmed to have a strong growth inhibitory effect against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, and its usefulness as a treatment for infections caused by these bacteria has been reported (Non-Patent Documents 2 and 3). In addition, it has been reported that Sho-seiryu-to has an antibacterial effect against Staphylococcus aureus (Non-Patent Document 4). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Pharmacogenet. J., 8, 20-23(2016). [Non-Patent Document 2] Traditional & Kampo Medicine, 4(2), 111-115(2017). [Non-Patent Document 3] Proceedings of the 33rd Annual Meeting of the Japanese Society of Traditional Chinese Medicine, p. 61 [Non-Patent Document 4] Nikki Eclipse Bulletin, 48(5), 401-407(1997) Summary of the Invention [Problem to be solved by the invention]

[0010] In order to effectively suppress the antibacterial resistance of S. aureus, it is essential not to expose S. aureus to an environment that is difficult for it to grow in, even when an antibacterial agent is used, in which it would acquire antibacterial resistance. In other words, it is essential to exert a necessary antibacterial effect on the target bacteria while at the same time not exerting an antibacterial effect on normally resident S. aureus so as not to cause the bacteria to acquire antibacterial resistance, i.e. selective antibacterial action.

[0011] In this regard, Shini-seihai-to has antibacterial properties against Streptococcus pneumoniae and is therefore useful as an antibacterial agent targeting Streptococcus pneumoniae, but considering that it also has strong antibacterial properties against Staphylococcus aureus, it cannot be used for the purpose of selective antibacterial treatment.

[0012] Therefore, an object of the present invention is to provide an antibacterial agent that does not exhibit antibacterial activity against normally resident Staphylococcus aureus, but exhibits selective antibacterial activity against target bacteria. [Means for solving the problem]

[0013] As a result of intensive research, the present inventor has found that by using a specific herbal extract containing Shini-seihai-to at a specific low dose, selective antibacterial activity can be achieved that exhibits the necessary antibacterial activity against the target bacteria while at the same time not exhibiting antibacterial activity against Staphylococcus aureus. Based on this finding, the present invention has been completed through further research.

[0014] That is, the present invention provides the following aspects. Item 1. A medicine containing an extract of a herbal medicine selected from the group consisting of Shini-seihai-to, Keigaku-renkyo-to, Kakkonto-ka-senkyu-shini, and Sho-seiryu-to; The dose of the extract in terms of the original herbal medicine is 21 g / day or less for Shini Seihai Tang, 21.38 g / day or less for Keikei Renkyoto, 18 g / day or less for Kakkonto Ka Senkyu Shini, and 20.3 g / day or less for Shoseiryuto; and An antibacterial agent that does not target resident Staphylococcus aureus. Item 2. The antibacterial agent described in Item 1, which is applied to subjects who have taken an antibacterial agent with antibacterial activity against Staphylococcus aureus within the past year. Item 3. The antibacterial agent according to Item 1 or 2, which is used against upper respiratory tract infections and inflammation caused thereby. Item 4. The antibacterial agent according to Item 1 or 2, which is used against oral infections, skin infections, and lower respiratory tract infections, as well as inflammation caused by these infections. Item 5. The antibacterial agent according to any one of Items 1 to 4, which targets bacteria selected from the group consisting of Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium, Clostridium sobrinus, and Propionibacterium acnes. Effect of the Invention

[0015] According to the present invention, there is provided an antibacterial agent that does not exhibit antibacterial activity against normally resident Staphylococcus aureus and exhibits selective antibacterial activity against target bacteria, which is expected to suppress the acquisition of antibacterial resistance by Staphylococcus aureus. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The antibacterial agent of the present invention contains an extract of a traditional Chinese medicine selected from the group consisting of Shini-seihai-to, Keigaku-renkyo-to, Kakkonto-ka-senkyu-shini, and Sho-seiryu-to, is used at a prescribed dosage, and is characterized in that it does not target Staphylococcus aureus.

[0017] Active ingredients As for Shini Seihaito, the herbal prescription described in "New Guide to General Kampo Prescriptions" (edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparations Association, published by Jiho Co., Ltd.) or "Standards for Approval of the Manufacturing and Sale of General Kampo Preparations (Attachment)" (Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, April 1, 2017) is preferable, and examples of the herbal medicine mixture include Shini, Chimo, Byakugo, Scutellaria, Sanshishi, Bakumondou, Sekko, Citrus Rhizome, and Biwayo.

[0018] More specific examples of the mixed herbal medicines constituting Shini Seihaito include the following weight mixing ratios of Shini, Chimo, Byakugo, Scutellaria, Sanshishi, Bakumondou, Sekko, Citrus aurantium, and Biwayo: Shini 2.0-3.0 parts by weight, Chimo 3.0 parts by weight, Byakugo 3.0 parts by weight, Scutellaria 3.0 parts by weight, Sanshishi 1.5-3.0 parts by weight, Bakumondou 5.0-6.0 parts by weight, Sekko, The preferred compositions are 3.0 parts by weight of Chinese laurel, 3.0 parts by weight of Timothys Root, 3.0 parts by weight of Byakugo, 3.0 parts by weight of Scutellaria Baicalensis, 1.5 parts by weight of Sanshishi, 6.0 parts by weight of Bakumondou, 6.0 parts by weight of Gypsum, 1.5 parts by weight of Chinese laurel, and 1.0 part by weight of Biwayo.

[0019] As for Keigakurenkyoto, the Kampo prescription described in "New Guide to General Kampo Prescriptions" (Edited by Goda Yukihiro and Hakamzuka Takashi, Edited by the Japan Kampo Herbal Medicine Preparations Association, Published by Jiho Co., Ltd.) or "Standards for Approval of Manufacturing and Marketing of General Kampo Preparations (Attachment)" (Pharmaceutical and Food Safety Bureau, Ministry of Health, Labor and Welfare, April 1, 2017) is preferable, and includes a mixture of herbs consisting of Angelica Root, Peony Root, Cnidium Root, Rehmannia Root, Scutellaria Root, Phellodendron Bark, Sanshishi, Forsythia Root, Celastrus Root, Boufu Root, Mentha Root, Phellinus Root, Licorice Root, Bupleurum Root, Angelica Root, and Platycodon Root. Some letters do not include Rehmannia Root, Coptis Root, Phellodendron Bark, and / or Mint.

[0020] As a more specific example of the mixed herbal medicines constituting Keigakurenkyoto, the weight ratio of Angelica Root, Peony Root, Cnidium Root, Rehmannia Root, Coptis Root, Scutellaria Root, Phellodendron Bark, Sanshishi Root, Forsythia Root, Keigai Root, Boufu Root, Mint Root, Phellodendron Root, Licorice Root, Bupleurum Root, Angelica Root, Platycodon Root, and Platycodon Root is 1.5 parts by weight, Angelica Root 1.5 parts by weight, Cnidium Root 1.5 parts by weight, Rehmannia Root 1.5 parts by weight, Coptis Root 1.5 parts by weight, Scutellaria Root 1.5 parts by weight, Phellodendron Root 1.5 parts by weight, Boufu Root 1.5 parts by weight, Mint Root 1.5 parts by weight, Phellodendron Root 1.5 parts by weight, Licorice Root 1. The preferred are 1.5 parts by weight of Angelica Root, 1.5 parts by weight of Peony Root, 1.5 parts by weight of Cnidium Root, 1.5 parts by weight of Rehmannia Root, 1.5 parts by weight of Coptis Rhizome, 1.5 parts by weight of Scutellaria Root, 1.5 parts by weight of Phellodendron Bark, 1.5 parts by weight of Sanshi Fruit, 1.5 parts by weight of Forsythia Root, 1.5 parts by weight of Japanese Sprout, 1.5 parts by weight of Garlic Root, 1.5 parts by weight of Mentha Root, 1.5 parts by weight of Phellodendron Root, 1.5 parts by weight of Licorice Root, 2.5 parts by weight of Bupleurum Root, 2.5 parts by weight of Angelica Root, 2.5 parts by weight of Angelica Root, and 2.5 parts by weight of Platycodon Grandiflorum.

[0021] As for Kakkonto-ka-senkyu-shini, the Kampo prescription described in "New Guide to General Kampo Prescriptions" (Edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparations Association, published by Jiho Co., Ltd.) or "Standards for Approval of the Manufacturing and Sale of General Kampo Preparations (Attachment)" (Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, April 1, 2017) is preferable, and examples of the mixed herbal medicines include Kakkon, Ephedra Root, Taisou, Cinnamon Bark, Peony Root, Glycyrrhiza Root, Shokyo, Cnidium Root, and Shini.

[0022] As a more specific example of the mixed herbal medicines constituting Kakkonto-ka-senkyu-shini, the weight ratio of Kakkon, Ephedra, Taiso, Cinnamon, Peony, Licorice, Ginger, Cnidium, and Shini is as follows: Kakkon 4.0-8.0 parts by weight, Ephedra 3.0-4.0 parts by weight, Taiso 3.0-4.0 parts by weight, Cinnamon 2.0-3.0 parts by weight, Peony 2.0-3.0 parts by weight, Licorice 2.0 parts by weight, Sho Examples of the composition include 1.0 to 1.5 parts by weight of Angelica Root, 2.0 to 3.0 parts by weight of Cnidium Root, and 2.0 to 3.0 parts by weight of Radix Aurantium Root, and preferably 4.0 parts by weight of Pueraria Root, 4.0 parts by weight of Ephedra Root, 3.0 parts by weight of Atractylodes Root, 2.0 parts by weight of Cinnamon Bark, 2.0 parts by weight of Peony Root, 2.0 parts by weight of Licorice Root, 1.0 part by weight of Zingiber Root, 3.0 parts by weight of Cnidium Root, and 3.0 parts by weight of Radix Aurantium Root.

[0023] As Sho-seiryu-to, the herbal prescription described in "New Guide to General Kampo Prescriptions" (Edited by Goda Yukihiro and Hakamzuka Takashi, edited by the Japan Kampo Herbal Medicine Preparations Association, published by Jiho Co., Ltd.) or "Standards for Approval of the Manufacturing and Sale of General Kampo Preparations (Attachment)" (Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare, April 1, 2017) is preferable, and examples of the herbal medicine include a mixture of Ephedra Root, Peony Root, Kankyo Root, Glycyrrhiza Root, Cinnamon Bark, Saishin Root, Gomishi Root, and Pinellia Root.

[0024] More specific examples of the mixed herbal medicines that make up Shoseiryuto include 2.0 to 3.5 parts by weight of Ephedra Root, 2.0 to 3.5 parts by weight of Peony Root, 2.0 to 3.5 parts by weight of Kankyo, 2.0 to 3.5 parts by weight of Licorice, 2.0 to 3.5 parts by weight of Cinnamon Bark, 2.0 to 3.5 parts by weight of Saishin, 1.0 to 3.0 parts by weight of Gomizushi, and 3.0 to 8.0 parts by weight of Pinellia Sinensis, and preferably 3.0 parts by weight of Ephedra Root, 3.0 parts by weight of Peony Root, 3.0 parts by weight of Kankyo, 3.0 parts by weight of Licorice, 3.0 parts by weight of Cinnamon Bark, 3.0 parts by weight of Saishin, 3.0 parts by weight of Gomizushi, and 6.0 parts by weight of Pinellia Sinensis.

[0025] The extract of Shini-sei-hai-to, the extract of Gekkei-ren-kyo-to, the extract of Kakkon-to-ka-senkyu-shini-to, and the extract of Sho-sei-ryu-to can be obtained as an extract liquid by extracting the above-mentioned mixed herbal medicines and concentrating the obtained extract liquid as necessary, or the extract liquid can be obtained as an extract powder by drying the extract liquid.

[0026] In the production of Shini-sei-hai-to extract, Kei-kei-ren-kyo-to extract, Kakkon-to-ka-sen-kyu-shini extract, and Sho-sei-ryu-to extract, the extraction solvent used in the extraction process is not particularly limited, but for example, water or aqueous ethanol, preferably water. In addition, the drying process is also not particularly limited, and includes known methods, such as the spray drying method, and the method of adding a suitable adsorbent (e.g., silicic anhydride, starch, etc.) to the soft extract with the increased concentration of the extract liquid to make it into adsorbed powder, etc.

[0027] The extracts of Shin'i-seihai-to, Gekkei-ren-kyo-to, Kakkon-to-ka-senkyu-shin'i, and Sho-seiryu-to used in the present invention may be extracts prepared by the above-mentioned methods or commercially available extracts.

[0028] In the antibacterial agent of the present invention, the above-mentioned herbal extracts may be used alone or in combination of two or more.

[0029] In the antibacterial agent of the present invention, the content of the extract of a herbal medicine selected from the group consisting of Shini-seihai-to, Kei-kei-ren-kyo-to, Kakkon-to-ka-sen-kyu-shini, and Sho-sei-ryu-to is not particularly limited as long as it exhibits the effects of the present invention, but may be, for example, 1 to 100% by weight in terms of the amount of dried extract. In terms of the amount of dried extract, when a dried extract (extract powder) is used, it is the amount itself, and when an extract liquid or soft extract is used, it is the amount converted into the amount remaining after removing the solvent. In addition, when the dried extract powder contains additives such as adsorbents added during production, it is the amount excluding the additives.

[0030] Other ingredients The antibacterial agent of the present invention may contain other pharmacological ingredients, if necessary, in addition to the above-mentioned herbal medicine. The type of such pharmacological ingredients is not particularly limited, but examples thereof include antacids, stomachics, digestive agents, intestinal regulators, antispasmodics, mucosal repair agents, anti-inflammatory agents, astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedatives, hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents (other than the above-mentioned active ingredients), vasoconstrictors, vasodilators, local anesthetics, herbal medicines, herbal extracts (other than the above-mentioned active ingredients), vitamins, menthols, etc. These pharmacological ingredients may be used alone or in combination of two or more. The content of these pharmacological ingredients may be appropriately set from known ones according to the type of pharmacological ingredients to be used, etc.

[0031] The antibacterial agent of the present invention may contain pharma- ceutically acceptable bases and additives, etc., as necessary, in order to prepare the agent into a desired dosage form. Examples of such bases and additives include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, water, oils and fats, waxes, hydrocarbons, fatty acids, higher alcohols, esters, water-soluble polymers, surfactants, metal soaps, lower alcohols, polyhydric alcohols, pH adjusters, buffers, antioxidants, UV inhibitors, preservatives, flavorings, fragrances, powders, thickeners, dyes, and chelating agents. These bases and additives may be used alone or in combination of two or more. The content of these bases and additives may be appropriately set from known ones according to the type of additive component used and dosage form, etc.

[0032] Dosage form The dosage form of the antibacterial agent of the present invention is not particularly limited, and may be any of tablets, granules, powders, pills, capsules, films, liquids (drinks, mouthwashes), etc. Among these dosage forms, in the case of internal use, tablets and granules are preferred from the viewpoint of ease of administration, and in the case of external use, mouthwash is preferred from the viewpoint of ease of application. These dosage forms can be prepared using pharma- ceutically acceptable base materials and additives, and the types and amounts of the base materials and additives are also known in the field of formulation technology.

[0033] Purpose The antibacterial agent of the present invention does not exhibit antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, and is therefore used for the purpose of selective antibacterial activity that does not target resident Staphylococcus aureus while exerting antibacterial activity against target bacteria. Resident state refers to a state in which resident bacteria are not abnormally proliferating, and resident Staphylococcus aureus refers to Staphylococcus aureus in a state in which it is not abnormally proliferating to the extent that it does not cause a Staphylococcus aureus infection. Preferably, the antibacterial agent of the present invention is used for the purpose of selective antibacterial activity that does not target resident Staphylococcus aureus and resident methicillin-resistant Staphylococcus aureus while exerting antibacterial activity against target bacteria.

[0034] The target bacteria is not particularly limited as long as it is a bacterium that causes infections and inflammations caused by bacteria. Examples of infections and inflammations caused by bacteria include upper respiratory tract infections, oral infections, skin infections, circulatory system infections, and / or lower respiratory tract infections, and / or inflammations caused by them. Examples of oral infections and inflammations caused by them include periodontal disease, gingivitis, dental caries, etc.; examples of upper respiratory tract infections and inflammations caused by them include otorhinolaryngeal infections (sinusitis, rhinitis, nasal vestibular eczema, otitis media, etc.), tonsillitis, epiglottitis, pharyngitis, etc.; examples of skin infections and inflammations caused by them include eczema, acne vulgaris, etc.; examples of circulatory system infections and inflammations caused by them include sepsis, etc.; examples of lower respiratory tract infections and inflammations caused by them include bronchitis, bacterial pneumonia, etc., and preferably include upper respiratory tract infections, oral infections, skin infections, lower respiratory tract infections, and inflammations caused by them.

[0035] Examples of bacteria include gram-positive bacteria and gram-negative bacteria, etc. Specific examples of bacteria include Streptococcus mutans, Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus sobrinus, Streptococcus pneumoniae, Haemophilus influenzae, Propionibacterium acnes, etc.

[0036] The antibacterial agent of the present invention can be used for the purpose of improving the abnormal proliferation of the above-mentioned bacteria.

[0037] For example, when the antibacterial agent of the present invention is used internally, more specifically, it can be used for the purpose of improving (treating or inhibiting the progress of) the above-mentioned bacterial infections and inflammation caused by them. That is, the antibacterial agent of the present invention can be applied to patients who have developed the above-mentioned bacterial infections and inflammation caused by them. In this way, patients who have developed bacterial infections and inflammation caused by them have a weakened immune system and are already in a state where the causative bacteria are abnormally proliferating, so it is no longer possible to eliminate the bacteria by symptomatic treatment such as enhancing the immune system, and the symptoms cannot be effectively improved. Since the antibacterial agent of the present invention is an antibacterial agent that directly exhibits an antibacterial effect against the causative bacteria, it is expected to effectively improve the symptoms of the above-mentioned patients.

[0038] Furthermore, when the antibacterial agent of the present invention is applied externally (particularly in or outside the oral cavity), it can be used, more specifically, for the purpose of improving abnormal proliferation caused by the above-mentioned bacteria (particularly bacteria causing oral infections).

[0039] The antibacterial agent of the present invention does not exhibit antibacterial activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, and is therefore particularly useful when applied to subjects at high risk of developing drug resistance to Staphylococcus aureus. Specific examples of subjects at high risk of developing drug resistance to Staphylococcus aureus include subjects who have taken an antibacterial agent against Staphylococcus aureus within the past year. Antibacterial agents against Staphylococcus aureus include not only antibacterial agents that target Staphylococcus aureus, but also antibacterial agents that target bacteria other than Staphylococcus aureus and inevitably exhibit antibacterial activity against the non-target bacteria Staphylococcus aureus. Examples of such antibacterial agents include penicillin, cephalosporin, carbapenem, glycopeptide, oxazolidinone, lipopeptide, aminoglycoside, tetracycline, lincomycin, and / or rifamycin antibacterial agents.

[0040] Dosage / Usage The method of administration of the antibacterial agent of the present invention is not particularly limited, but preferred methods include oral administration (internal use) and intraoral administration (external use).

[0041] The dosage of the antibacterial agent of the present invention is, in terms of the amount of the original herbal medicine, 21 g / day or less for Shini-seihai-to extract, 21.38 g / day or less for Keigaku-renkyo-to extract, 18 g / day or less for Kakkonto-ka-senkyu-shini extract, and 20.3 g / day or less for Sho-seiryu-to extract, in order to express a selective antibacterial effect. The lower limit of the range of the dosage in terms of the original herbal medicine may be appropriately determined by a person skilled in the art within the range in which antibacterial activity is expressed, for example, 8.4 g / day or more for Shini-seihai-to extract, preferably 14 g / day or more for Keigaku-renkyo-to extract, 14.2 g / day or more for Kakkonto-ka-senkyu-shini extract, 12 g / day or more for Sho-seiryu-to extract, and 8.1 g / day or more for Sho-seiryu-to extract.

[0042] The dosage of the antibacterial agent of the present invention may be an amount equivalent to 2.25 g / day or less of the original herbal drug of Zhimo when Shini-sei-fei-to extract is used as the active ingredient of the antibacterial agent of the present invention; an amount equivalent to 1.13 g / day or less of the original herbal drug of Touki when Gekkei-renkyo-to extract is used as the active ingredient of the antibacterial agent of the present invention; or an amount equivalent to 1.5 g / day or less of the original herbal drug of Licorice when Kakkonto-ka-senkyu-shini extract is used as the active ingredient of the antibacterial agent of the present invention. The lower limit of the range of the amount of each of the above-mentioned herbal medicines in terms of the original herbal medicine may be appropriately determined by a person skilled in the art within the range in which the antibacterial agent of the present invention exhibits antibacterial properties. For example, when Shini Qing Fei Tang extract is used as the active ingredient of the antibacterial agent of the present invention, an amount equivalent to 0.9 g / day or more of Zhimo in terms of the original herbal medicine may be used; when Gekkei Forsythia Tang extract is used as the active ingredient of the antibacterial agent of the present invention, an amount equivalent to 0.75 g / day or more of Dong Qui in terms of the original herbal medicine may be used; when Kakkonto Ka Senkyu Shini extract is used as the active ingredient of the antibacterial agent of the present invention, an amount equivalent to 1 g / day of Licorice in terms of the original herbal medicine may be used.

[0043] The dosage of the antibacterial agent of the present invention may be, in terms of the amount of dry extract, 3.38g / day or less for Shini-seihai-to extract, 3.38g / day or less for Keigaku-renkyo-to extract, 3g / day or less for Kakkonto-ka-senkyu-shini extract, and 3.38g / day or less for Sho-seiryu-to extract, in order to exhibit selective antibacterial effect. The lower limit of the range of the dosage in terms of the amount of dry extract may be appropriately determined by a person skilled in the art within the range in which antibacterial activity is exhibited, for example, 1.35g / day or more, preferably 2.25g / day or more for Shini-seihai-to extract, 2.25g / day or more for Keigaku-renkyo-to extract, 2g / day or more for Kakkonto-ka-senkyu-shini extract, and 1.35g / day or more for Sho-seiryu-to extract.

[0044] The above dosages indicate the dosages per adult, more specifically, the dosages per 50 kg body weight.

[0045] The timing of administration of the antibacterial agent of the present invention is not particularly limited, and may be after waking up, before or after meals, between meals, or before going to bed, but for internal use, it is preferably before or between meals, and for external use (particularly for oral use), it is preferably after waking up, after meals, between meals, and / or before going to bed. It is also preferable to administer it three times a day, and the dose calculated based on the amount of dried extract is 2.5 g / day or less for Shini-sei-hai-to extract, preferably 2.25 g / day or less for Kei-gaku-ren-kyo-to extract, 2.25 g / day or less for Kakkon-to-ka-sen-kyu-shini extract, and 2.25 g / day or less for Sho-sei-ryu-to extract; the dose calculated based on the amount of raw herbal medicine is 14 g / day or less for Shini-sei-hai-to extract, 1 g / day or less for Kei-gaku-ren-kyo-to extract, and 1 g / day or less for Sho-sei-ryu-to extract. 4.25g / day or less, Kakkonto-ka-Senkyu-Shin'i extract 12g / day or less, and Shoseiryu-to extract 13.5g / day or less; Shini-seihai-to extract with a herbal equivalent of 1.5g / day or less, Gekkei-renkyoto extract with a herbal equivalent of 0.75g / day or less, and Kakkonto-ka-Senkyu-Shin'i extract with a herbal equivalent of 1g / day or less, may be administered twice a day (for example, twice a day in the morning and evening). Furthermore, in order to obtain the antibacterial effect of the present invention better, it is preferable to administer continuously for 5 days or more, preferably 1 week or more, and more preferably 2 weeks or more. Furthermore, in order to obtain the selective antibacterial effect better, the continuous administration period is preferably 4 weeks or less. EXAMPLES

[0046] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0047] [Test Example 1] 1. Preparation of Antimicrobial Agents 1-1. Shini-seihai-to extract A mixture of herbs with the composition shown in Table 1 was prepared, and 10 times the amount of water by weight was added, followed by extraction with stirring at approximately 100°C for 1 hour. The extract was then collected by centrifugation, concentrated under reduced pressure, and dried using a spray dryer to obtain 4.5 g of Shini-seihai-to extract (equivalent to the full prescribed amount). This Shini-seihai-to extract was used as an antibacterial agent targeting Streptococcus pneumoniae.

[0048] 1-2. Keigakurenkyoto Extract A mixture of herbs with the composition shown in Table 1 was prepared, and 20 times the amount of water by weight was added, followed by extraction with stirring at approximately 100°C for 1 hour. The extract was then collected by centrifugation, concentrated under reduced pressure, and dried using a spray dryer to obtain 4.5 g of Keigakurenkyoto extract (equivalent to the full prescribed amount). This Keigakurenkyoto extract was used as an antibacterial agent targeting Streptococcus pneumoniae.

[0049] 1-3. Kakkonto-ka-Senkyu-Shin-i Extract A mixture of herbs with the composition shown in Table 1 was prepared, and 20 times the amount of water by weight was added, followed by extraction with stirring at approximately 100°C for 1 hour. The extract was then collected by centrifugation, concentrated under reduced pressure, and dried using a spray dryer to obtain 4.0 g of Kakkonto-ka-senkyu-shini extract (equivalent to the full prescribed amount). This Kakkonto-ka-senkyu-shini extract was used as an antibacterial agent targeting Streptococcus pneumoniae.

[0050] 1-4. Shoseiryuto extract A mixture of herbs with the composition shown in Table 1 was prepared, and 10 times the amount of water by weight was added, followed by extraction with stirring at approximately 100°C for 1 hour. The extract was then collected by centrifugation, concentrated under reduced pressure, and dried using a spray dryer to obtain 4.0 g of Shini-seihai-to extract (equivalent to the full prescribed amount). This Sho-seiryu-to extract was used as an antibacterial agent targeting Streptococcus pneumoniae.

[0051] [Table 1]

[0052] 2. Antibacterial testing In order to evaluate the inhibitory effect against bacterial proliferation on the skin and mucous membranes, an antibacterial test was carried out using an agar medium as follows.

[0053] In a sterile petri dish with an inner diameter of 90 mm, 1 × 10 6 ~10 71 mL of bacterial solution containing CFU / mL of bacteria (Staphylococcus aureus, Staphylococcus methicillinii, and Streptococcus pneumoniae) was added, and 15 g of normal agar medium heated to 45°C was added thereto, mixed thoroughly, and then left at room temperature to allow the agar to solidify while evaporating excess water. Next, a sterilized filter paper with a diameter of 12 mm that had been impregnated with the amount of extract shown in "Amount added to filter paper" in Tables 2 to 5 and dried was placed in the center of the petri dish and cultured for 24 to 48 hours.

[0054] The "amount added to filter paper" shown in Tables 2 to 5 was derived as the amount of the extract exposed to the skin and mucosal tissues by taking the "dosage" shown in Tables 2 to 5 based on the following items. In other words, the antibacterial effect confirmed by the "amount added to filter paper" shown in Tables 2 to 5 indicates the antibacterial effect expressed in the body when the "dosage" shown in Tables 2 to 5 is taken.

[0055] For example, the dose (equivalent to the dry extract) of the full-dose formulation of Shini-seihai-to extract is 4.5 g / day, which is usually administered in three separate doses per day. Meanwhile, the blood volume of a human is 1 / 13 of the body weight, and is about 4 L for a 50 kg adult. In other words, when Shini-seihai-to extract is administered in three separate doses per day, the blood concentration of the extract at each dose is about 0.38 mg / mL (= 1.5 g / 4 L). Here, the blood flow rate per 1 g of nasal mucosa tissue is about 1.2 mL / min (Otorhinolaryngology and Clinical Medicine, Vol. 37, p. 1180-1186, 1991), so the blood flow rate per 15 g of tissue is about 18 mL / min. Since there is no significant difference in blood flow rate between the skin and mucosa tissues, when a full-dose formulation of Shini-seihai-to extract is administered in one dose, 6.8 mg of extract (= 0.38 mg x 18 mL) is exposed per minute per 15 g of tissue. Therefore, in the case of Shini-seihai-to extract, the amount added to 15 g of agar medium (amount added to filter paper) per dose of 4.5 g / day was 6.8 mg (Comparative Example 1). In addition, the amount added was 5.1 mg (Example 1) as the amount equivalent to 75% of the full dose prescription, 3.4 mg (Example 2) as the amount equivalent to 50% of the full dose prescription, and 2.0 mg (Example 3) as the amount equivalent to 30% of the full dose prescription. The amounts added to filter paper were determined in the same manner for Keigakurenkyoto extract (full dose prescription dose (dry extract equivalent) is 4.5 g), Kakkonto-ka-senkyu-shini extract (full dose prescription dose (dry extract equivalent) is 4.0 g), and Sho-seiryu-to extract (full dose prescription dose (dry extract equivalent) is 4.0 g).

[0056] As a result of the culture, the width of the halo (inhibition zone) formed around the filter paper was calculated using the following formula, and the antibacterial activity of the extract against each bacterium was evaluated based on the following evaluation criteria. The results are shown in Tables 2 to 5.

[0057]

number

[0058] (Evaluation criteria for antibacterial activity) -: No halo +: Halo width is 1~2mm ++: Halo width is 3~4mm +++: Halo width is 5-6mm

[0059] [Table 2]

[0060] [Table 3]

[0061] [Table 4]

[0062] [Table 5]

[0063] As is clear from Tables 2 to 5, Shini-seihai-to, Keigairengyo-to, Kakkonto-ka-senkyu-shini, and Sho-seiryu-to were found to act as antibacterial agents against pneumococcus. Among these, Shini-seihai-to, Keigairengyo-to, Kakkonto-ka-senkyu-shini, and Sho-seiryu-to (Comparative Examples 1 to 4) at full doses all exhibited antibacterial effects not only against the target bacterium Streptococcus pneumoniae, but also against non-target bacteria Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. In other words, when these herbal extracts are used as antibacterial agents, full doses of the herbal extracts pose a risk that Staphylococcus aureus and methicillin-resistant Staphylococcus aureus will acquire antibiotic resistance. On the other hand, Shini-seihai-to, Keigaku-renkyo-to, Kakkonto-ka-senkyu-shini, and Sho-seiryu-to (Examples 1 to 10), all prescribed in doses less than the full dose prescription, exhibited antibacterial effects against the target bacteria Streptococcus pneumoniae, but did not exhibit antibacterial effects against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, which are not the target bacteria.

[0064] Test Example 2 As subjects with a high risk of developing drug resistance to Staphylococcus aureus, 11 sinusitis patients (male and female, aged 20s to 40s) who had taken at least two types of antibiotics with antibacterial activity against Staphylococcus aureus (penicillins, cephalosporins, carbapenems, glycopeptides, oxazolidinones, lipopeptides, aminoglycosides, tetracyclines, lincomycins, and rifamycins) within the past year were selected. These subjects were given Shini-seihai-to extract, prepared from the herbal mixture shown in Test Example 1, at a dose of 2.25 g / day in terms of dried extract (14 g / day in terms of raw herbal medicine, 1.5 g / day in terms of raw herbal medicine), three times a day for seven days. After seven days, the subjects were asked to answer questions about changes in the viscosity and / or color of purulent nasal discharge, and changes in symptoms of nasal congestion and / or shortness of breath.

[0065] Purulent rhinorrhea indicates that the mucous membrane is infected with bacteria, and the decrease in viscosity and lightening of the color of purulent rhinorrhea indicates that bacterial growth is suppressed. As a result of taking Shini-seihai-to extract, the decrease in viscosity and / or lightening of the color of purulent rhinorrhea was confirmed in 7 out of 11 subjects. In addition, 8 out of 11 subjects showed improvement in nasal congestion, and 7 out of 11 subjects showed improvement in shortness of breath. Furthermore, 10 out of 11 subjects responded that at least one of the following was observed: decrease in viscosity and / or lightening of the color of purulent rhinorrhea, improvement in nasal congestion, and improvement in shortness of breath.

[0066] Test Example 3 Three adult males were administered the Shini-seihai-to extract prepared in Test Example 1 at a dose of 2.25 g / day in terms of dry extract (14 g / day in terms of raw herbal medicine, 1.5 g / day in terms of raw herbal medicine of Zhimo) three times a day for three days. Before and after administration, the nasal cavity was swabbed with a sterile cotton swab, and DNA was extracted from the bacteria attached to the cotton swab using a QIAamp DNA Mini Kit (Qiagen). Then, Amplicon PCR was performed using an Ion 16S Metagenomics Kit (Thermo Fisher), and the next-generation sequencing of the 18srRNA region was used to identify the bacterial species and calculate the number of bacteria that appeared (the relative number of bacteria after administration when the number of bacteria before administration is set to 100). The results are shown in Table 6.

[0067] [Table 6]

[0068] As is clear from Table 6, the number of Staphylococcus aureus bacteria did not change before and after administration, whereas the number of Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus mutans, Clostridium sobrinus, Fusobacterium spp., and Propionibacterium acnes bacteria was clearly reduced in all three subjects. This confirmed that Shini-seihai-to extract has selective antibacterial properties that do not target normal Staphylococcus aureus bacteria.

[0069] Test Example 4 Stickiness in the mouth is caused by the abnormal proliferation of oral bacteria such as periodontal disease bacteria and dental caries bacteria in saliva, and causes bad breath and discomfort, as well as oral infections such as periodontal disease, gingivitis, and tooth decay, or inflammation due to these. Therefore, eight subjects (men and women in their 20s and 30s) who were concerned about stickiness in the mouth were asked to rinse their mouths with 50 mL of tap water after breakfast and with half the amount of the Shini-seihai-to extract prepared in Test Example 1, dissolved in 100 mL of tap water at 2.25 g (14 g in terms of raw herbal medicine, 1.5 g in terms of raw herbal medicine) in 2.25 g in terms of dried extract, after lunch. The strength of stickiness in the mouth, bad breath, and pleasantness / unpleasantness in the mouth were evaluated after 4 hours. The strength of the bad breath was evaluated by the same third party on a 9-point scale from -4 to 4, and the strength of stickiness and pleasantness / unpleasantness were evaluated by the subject himself on a 9-point scale from -4 to 4. The scores range from -4 to 4, with 0 being "neither good nor bad," and the higher the score, the greater the stickiness in the mouth, the stronger the bad breath, and the more unpleasant the feeling in the mouth, while the lower the score, the less the stickiness in the mouth, the stronger the bad breath, and the more unpleasant the feeling in the mouth. It is said that oral bacteria, such as periodontal disease bacteria and tooth decay bacteria, grow by feeding on food debris in the mouth and produce sticky mucus four hours after a meal. In other words, stickiness in the mouth four hours after a meal indicates that bacteria have abnormally proliferated after a meal, and improvement indicates that bacterial proliferation has been suppressed. The results are shown in Table 7.

[0070] [Table 7]

[0071] As shown in Table 7, by rinsing the mouth with Shini-seihai-to extract, stickiness was significantly improved, and bad breath and discomfort were also significantly improved. In other words, it was shown that the proliferation of bacteria in the oral cavity was suppressed.

[0072] Test Example 5 Periodontal disease bacteria and dental caries bacteria grow in the oral cavity while sleeping. Therefore, eight subjects (men and women in their 20s and 30s) who were concerned about stickiness in the oral cavity were asked to rinse their mouths with 50 mL of tap water within one hour of waking up, and then their tongues were swabbed with a sterile cotton swab according to the instruction manual of the Panasonic bacteria counter (product number: DU-AA01NP-H) to measure the number of bacteria. Next, within one hour of waking up the next day, the subjects were asked to rinse their mouths with half the amount of the Shini-seihai-to extract prepared in Test Example 1, which was dissolved in 100 mL of tap water at 2.25 g (14 g in terms of raw herbal medicine, 1.5 g in terms of raw herbal medicine of Zhimo), and after rinsing their mouths lightly, the number of bacteria was measured in the same manner as the previous day. After waking up, the subjects were not allowed to brush their teeth or eat or drink until the end of the test. The results are shown in Table 8.

[0073] [Table 8]

[0074] As is clear from Table 8, mouthwash using Shini-seihai-to extract reduced the number of bacteria in the oral cavity, indicating an antibacterial effect against oral bacteria.

Claims

1. Contains extract of Shini Seihaitou, For adults, the dose of the extract in terms of raw herbal medicine is 8.4 g / day or more and 21 g / day or less, taken three times a day; An antibacterial agent for use in an application that targets bacteria selected from the group consisting of Streptococcus mutans, Fusobacterium, Clostridium sobrinus, Propionibacterium acnes, and Haemophilus influenzae, and does not target Staphylococcus aureus.

2. The present invention comprises an extract of a herbal medicine selected from the group consisting of Keigakurenkyoto, Kakkonto-ka-senkyu-shini, and Shoseiryu-to, For adults, the dose of the extracts in terms of the raw herbal medicine equivalent is 14.2 g / day to 21.38 g / day for Keikakurenkyoto, 12 g / day to 18 g / day for Kakkonto-ka-senkyu-shini, and 8.1 g / day to 20.3 g / day for Sho-seiryu-to, taken three times a day. An antibacterial agent that targets Streptococcus pneumoniae and is used in applications that do not target Staphylococcus aureus.

3. The antibacterial agent according to claim 1 or 2, which is applied to a subject who has taken an antibacterial agent having antibacterial activity against Staphylococcus aureus within the past year.

4. The antibacterial agent according to claim 1 for use against upper respiratory tract infections and inflammation caused by bacteria selected from the group consisting of Streptococcus mutans, Fusobacterium, Clostridium sobrinus, Propionibacterium acnes, and Haemophilus influenzae.

5. The antibacterial agent according to claim 1, for use against at least one of oral infections, skin infections, and lower respiratory tract infections, and inflammation caused by these infections, caused by bacteria selected from the group consisting of Streptococcus mutans, Fusobacterium, Clostridium sobrinus, Propionibacterium acnes, and Haemophilus influenzae.

6. The antibacterial agent according to claim 2 for use against upper respiratory tract infections and inflammation caused by pneumococcus.

7. The antibacterial agent according to claim 2, for use against at least one of oral infections, skin infections, and lower respiratory tract infections caused by pneumococcus, and inflammation caused by these infections.

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