WO2019098241A1 - Pharmaceutical composition for mastitis, and medical treatment method - Google Patents

Pharmaceutical composition for mastitis, and medical treatment method Download PDF

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WO2019098241A1
WO2019098241A1 PCT/JP2018/042148 JP2018042148W WO2019098241A1 WO 2019098241 A1 WO2019098241 A1 WO 2019098241A1 JP 2018042148 W JP2018042148 W JP 2018042148W WO 2019098241 A1 WO2019098241 A1 WO 2019098241A1
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ozone
mastitis
pharmaceutical composition
glycerin
present
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PCT/JP2018/042148
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French (fr)
Japanese (ja)
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岡本　芳晴
武志 柄
亮 西村
和記 原田
塩田　剛太郎
明 岡本
岡本　太郎
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株式会社メディプラス製薬
国立大学法人鳥取大学
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Priority to JP2019554258A priority Critical patent/JPWO2019098241A1/en
Publication of WO2019098241A1 publication Critical patent/WO2019098241A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea

Abstract

Provided is a new pharmaceutical composition which is for mastitis and which is safe and has excellent handling properties and economic efficiency. This pharmaceutical composition for mastitis includes an ozone-dissolved glycerin and is applicable to the treatment of mastitis. A subject to be administered with this pharmaceutical composition for mastitis comprises, for example, humans, and non-human animals excluding humans, including milking animals such as cattle, goat, sheep, etc.

Description

乳房炎用医薬組成物、および治療方法Pharmaceutical composition for mastitis and method of treatment
　本発明は、乳房炎用医薬組成物、およびそれを用いた治療方法に関する。 The present invention relates to a pharmaceutical composition for mastitis and a method of treatment using the same.
　乳房炎とは、乳房内に侵入した微生物の定着と増殖によって起きる乳管系や乳腺組織の炎症をいい、哺乳動物において大きな問題となっている。特に乳牛においては、疾病の３割を占め、生産乳量の減少や乳質の低下等の経済的な問題を引き起こしている。 Mastitis refers to inflammation of breast duct system and mammary gland tissue caused by colonization and proliferation of microbes invading the breast, and is a major problem in mammals. Particularly in dairy cows, it accounts for 30% of the disease, causing economic problems such as reduction of milk production and reduction of milk quality.
　乳房炎の治療については、広く抗生物質が用いられているが、抗生物質の抗菌スペクトルの狭さや、耐性菌の出現によって、十分な治療効果が得られないこともあった。また、乳牛に抗生物質を用いた場合、乳における薬剤残留によって、牛乳が出荷停止となり経済的損失が大きく、抗生物質の代替となる殺菌剤のニーズがあった。 Antibiotics are widely used for the treatment of mastitis, but due to the narrowing of the antimicrobial spectrum of antibiotics and the appearance of resistant bacteria, sufficient therapeutic effects may not be obtained. In addition, when antibiotics are used in dairy cows, milk residue due to drug residue in milk stops the shipment of the milk and there is a large economic loss, and there is a need for a bactericide that substitutes for antibiotics.
　抗生物質の代替となる殺菌剤として、オゾンガスを用いて乳牛の乳房炎を治療する試みがなされてきた（特許文献１～４、非特許文献１～３）。 Attempts have been made to treat mastitis in dairy cows using ozone gas as a bactericide to replace antibiotics (Patent Documents 1 to 4, Non-patent Documents 1 to 3).
　オゾンガスは、病原微生物の種類を選ぶことなく作用し、また、抗生物質の場合のように薬剤残留による出荷への影響がないとされており（特許文献１）、抗生物質に代替し得る治療効果が期待できる（非特許文献１および２）。しかしながら、オゾンガスは、化学的に不安定であるばかりでなく、強力な酸化力を有することから、人体に有毒であり、取り扱いが困難である。しかも、オゾン発生装置等の大掛かりな装置が必要となり、簡便に用いることができないという欠点があった。 Ozone gas works without choosing the type of pathogenic microbes, and, like in the case of antibiotics, it is believed that drug residue does not affect shipment (Patent Document 1), and therapeutic effects that can be substituted for antibiotics Can be expected (non-patent documents 1 and 2). However, ozone gas is not only chemically unstable but also has strong oxidizing power, so it is toxic to human body and difficult to handle. In addition, a large-scale apparatus such as an ozone generator is required, and there is a disadvantage that it can not be used easily.
　オゾン発生装置を携帯型にすることも検討されてきたが（特許文献２）、装置が複雑化し、製造コストが高騰する虞がある。また、オゾンガスは化学的安定性の点で取り扱い性が悪いところ、オゾンガスを冷却することで劣化を抑制する試みがなされているが（特許文献３）、専用の気密性容器が必要となり、簡便に用いることができない。 Although making an ozone generator into a portable type has also been studied (Patent Document 2), there is a possibility that the apparatus becomes complicated and the manufacturing cost increases. In addition, although ozone gas has poor handleability in terms of chemical stability, attempts have been made to suppress deterioration by cooling the ozone gas (Patent Document 3), but a dedicated airtight container is required, which is convenient. It can not be used.
特開平９－１５４８６２号公報Unexamined-Japanese-Patent No. 9-154862 gazette 特開２００８－２８９５２３号公報JP 2008-289523 A 特開２００３－６３８０５号公報JP 2003-63805 特開平９－２８９９９５号公報Japanese Patent Application Laid-Open No. 9-289995 特開２００５－２３２０９４号公報JP, 2005-232094, A 特開２０１１－４２６８９号公報JP 2011-42689 A
　オゾンガス以外の態様、例えば、オゾン水やオゾン軟膏の態様について言及されている文献も存在するが（特許文献４、非特許文献３）、実際に乳房炎の治療効果を示したとされる報告はなされていない。また、オゾン溶存グリセリンの形態が、創傷用の外用剤としての用途の報告にすぎない（特許文献５および６）。そして、急性大腸菌性乳房炎に対してオゾン水を用いて乳房洗浄を行った場合は、生理食塩水で乳房洗浄を行った場合と有意差がないことが報告されている（非特許文献４）。このように、オゾンを利用した乳房炎の治療法は、未だ実用的なレベルには達しておらず、とりわけオゾンガス以外の態様においては、実質的な議論もなされていないのが現状である。 Although there are documents mentioning aspects other than ozone gas, for example, aspects of ozone water and ozone ointment (Patent Document 4 and Non-patent Document 3), it is reported that they actually showed the therapeutic effect on mastitis. Not. In addition, the form of ozone dissolved glycerin is only a report of the use as an external preparation for wounds (Patent Documents 5 and 6). Then, it has been reported that there is no significant difference in the case of performing udder lavage with ozone water for acute coliform mastitis with lavage with physiological saline (Non-Patent Document 4) . Thus, the treatment of mastitis using ozone has not yet reached a practical level, and particularly in aspects other than ozone gas, no substantial discussion has been made at present.
　前述のように、乳房炎の治療においてオゾンガスを用いるためには、大掛かりな装置が必要となり、オゾンガスの化学的安定性、安全性等の観点から、取り扱いが容易ではない。このため、結局、乳房炎の治療においては、オゾンガスではなく、抗生物質を用いることを余儀なくされている。本発明者らは、現状では、抗生物質による耐性菌の出現の問題や乳における薬剤残留の問題等は、オゾンガスを用いることでは実質的には解決されていないことから、依然として、抗生物質の代替となる殺菌剤を得ることが急務であるとの認識を抱くに至った。すなわち、本発明の課題は、安全で、取り扱い性や経済性に優れた新しい乳房炎用医薬を提供することにある。 As described above, in order to use ozone gas in the treatment of mastitis, a large-scale device is required, and handling is not easy from the viewpoint of chemical stability, safety, etc. of ozone gas. For this reason, eventually, in the treatment of mastitis, it is forced to use antibiotics instead of ozone gas. The inventors of the present invention are still able to substitute antibiotics as the problem of emergence of antibiotic-resistant bacteria and the problem of drug residue in milk are not practically solved by using ozone gas at present. Came to realize that it is urgent to obtain a disinfectant that That is, the object of the present invention is to provide a new medicine for mastitis which is safe and excellent in handleability and economy.
　本発明者らは、かかる課題を解決するために鋭意研究を重ねる中で、オゾン溶存グリセリンを乳房炎に罹患した患畜に投与することによって、極めて効果的に乳房炎を治療することができることを見出し、本発明を完成するに至った。すなわち本発明は、以下に関する。 The present inventors have found that it is possible to treat mastitis extremely effectively by administering ozone-dissolved glycerin to a patient suffering from mastitis while conducting intensive studies to solve such problems. The present invention has been completed. That is, the present invention relates to the following.
　本発明の乳房炎用医薬組成物は、オゾン溶存グリセリンを含む。 The pharmaceutical composition for mastitis of the present invention comprises ozone-dissolved glycerin.
　本発明の動物の乳房炎の治療方法は、前記本発明の乳房炎用医薬組成物を乳房内へ投与する投与工程を含む。 The method for treating mastitis of an animal of the present invention comprises the administration step of administering the pharmaceutical composition for mastitis of the present invention into the breast.
　本発明のオゾン溶存グリセリンは、乳房炎の治療に使用するためのオゾン溶存グリセリンである。 The ozone-dissolved glycerin of the present invention is ozone-dissolved glycerin for use in the treatment of mastitis.
　本発明の医薬組成物は、乳房炎を治療できる。本発明の医薬組成物は、特に、有毒で化学的に不安定なオゾンガスを用いないことから、安全性および取り扱い性に優れている。また、本発明の医薬組成物は、オゾンガスを用いた場合に問題となっていたオゾンガス発生装置等の特別な機器を用意する必要がなく、比較的低コストで、簡便に用いることができる。 The pharmaceutical composition of the present invention can treat mastitis. The pharmaceutical composition of the present invention is excellent in safety and handleability, in particular, because it does not use toxic and chemically unstable ozone gas. In addition, the pharmaceutical composition of the present invention does not have to prepare a special device such as an ozone gas generator which has been a problem when ozone gas is used, and can be used conveniently at relatively low cost.
　本発明は、オゾンガス以外の態様で、初めて乳房炎に対する治療効果を確認したものであり、乳房炎の治療におけるオゾンの利用について新たな途を拓くものである。また、本発明において有効成分であるオゾン溶存グリセリンは、これまで外用剤としての実用化に止まるものであって、オゾン溶存グリセリンの利用の側面においても新たな途を拓くものである。 The present invention is the first to confirm the therapeutic effect on mastitis in aspects other than ozone gas, and opens up new applications for the use of ozone in the treatment of mastitis. Further, ozone-dissolved glycerin, which is an active ingredient in the present invention, has only been put into practical use as an external preparation, and opens up new applications in terms of utilization of ozone-dissolved glycerin.
　本発明によれば、乳房炎の治療において、抗生物質の代替となる実用的な新たな医薬組成物を提供することができる。このため、本発明によれば、例えば、抗生物質のような耐性菌の問題を回避できる。また、本発明におけるオゾン溶存グリセリンは、オゾンとグリセリンからなり、例えば、乳中の薬剤残留による出荷停止の問題も回避できる。 According to the present invention, it is possible to provide a practical new pharmaceutical composition that is an alternative to antibiotics in the treatment of mastitis. Therefore, according to the present invention, the problem of resistant bacteria such as antibiotics can be avoided. In addition, ozone-dissolved glycerin in the present invention is composed of ozone and glycerin, and for example, the problem of suspension of shipment due to drug remaining in milk can be avoided.
＜医薬組成物＞
　本発明の医薬組成物は、前述のように、オゾン溶存グリセリンを含む乳房炎用医薬組成物である。（以下、「組成物」ともいう）。本発明の組成物は、乳房炎の有効成分として、オゾン溶存グリセリンを使用することが特徴であって、その他の構成については、何ら制限されない。 <Pharmaceutical composition>
The pharmaceutical composition of the present invention is, as described above, a pharmaceutical composition for mastitis containing ozone-dissolved glycerin. (Hereafter, it is also called "a composition"). The composition of the present invention is characterized by using ozone-dissolved glycerin as an active ingredient of mastitis, and the composition of the present invention is not limited in any way.
　本発明の組成物は、乳房炎に対する治療用の医薬組成物である。本発明において、「治療」とは、例えば、いわゆる、乳房炎の症状を緩和したり、乳房炎を治癒するための行為の他、乳房炎への罹患を防止する予防の行為の意味も含む。すなわち、本発明の組成物は、例えば、乳房炎の緩和、治癒、および予防のために使用でき、いずれか１つを目的として使用されてもよいし、２つ以上を目的として使用されてもよい。 The composition of the present invention is a pharmaceutical composition for the treatment of mastitis. In the present invention, the term "treatment" includes, for example, so-called alleviation of symptoms of mastitis and actions for curing mastitis, as well as the meaning of preventive actions for preventing the occurrence of mastitis. That is, the composition of the present invention can be used, for example, for alleviation, cure, and prevention of mastitis, and may be used for any one or two or more. Good.
　本発明の組成物は、例えば、有効成分のみからなる組成物でもよいし、さらに、有効成分以外の添加成分を含む組成物でもよい。前記有効成分は、例えば、オゾン溶存グリセリンのみからなってもよいし、オゾン溶存グリセリンの他に、さらに、他の有効成分を含んでもよいが、オゾン溶存グリセリンは、前述のような効果を奏することから、前記有効成分は、オゾン溶存グリセリンからなることが好ましい。 The composition of the present invention may be, for example, a composition consisting only of the active ingredient, or may be a composition further containing additives other than the active ingredient. The above-mentioned active ingredient may consist only of ozone dissolution glycerin, for example, and may contain other active ingredients besides ozone dissolution glycerin, but ozone dissolution glycerin exerts the above-mentioned effect. From the above, it is preferable that the active ingredient consists of ozone dissolved glycerin.
　本発明の組成物は、前記オゾン溶存グリセリンの他に、例えば、グリセリン以外の希釈物質をさらに含んでもよい。前記希釈物質は、例えば、水性溶媒であり、水、緩衝液、または生理的食塩水等が挙げられる。 The composition of the present invention may further contain, for example, a diluent other than glycerin in addition to the ozone-dissolved glycerin. The dilution substance is, for example, an aqueous solvent, such as water, buffer, or saline.
　本発明の組成物において、前記オゾン溶存グリセリンのオゾン濃度は、特に制限されず、例えば、治療の目的、対象動物の種類、乳房炎の程度等に応じて、適宜設定できる。前記オゾン溶存グリセリンのオゾン濃度は、例えば、１ｐｐｍ～１００００ｐｐｍであり、１０ｐｐｍ～１００００ｐｐｍであり、好ましくは、１００ｐｐｍ～４０００ｐｐｍである。また、本発明の組成物のオゾン濃度は、例えば、１～１００００ｐｐｍ、１０ｐｐｍ～１００００ｐｐｍであり、好ましくは、１００ｐｐｍ～４０００ｐｐｍである。 In the composition of the present invention, the ozone concentration of the ozone-dissolved glycerin is not particularly limited, and can be appropriately set according to, for example, the purpose of treatment, the type of target animal, the degree of mastitis and the like. The ozone concentration of the ozone-dissolved glycerin is, for example, 1 ppm to 10000 ppm, 10 ppm to 10000 ppm, and preferably 100 ppm to 4000 ppm. Further, the ozone concentration of the composition of the present invention is, for example, 1 to 10000 ppm, 10 ppm to 10000 ppm, preferably 100 ppm to 4000 ppm.
　本発明の組成物は、例えば、種々の乳房炎を治療できる。前記乳房炎としては、例えば、乳汁および乳房は正常であるが、体細胞の増加が認められ、有意な細菌が分離される潜在性乳房炎や、亜急性乳房炎、急性乳房炎、甚急性乳房炎等の臨床症状が認められる臨床性乳房炎や、臨床性乳房炎が治癒せずに進行した慢性乳房炎等があげられ、これらの乳房炎に対して、治療できる。 The compositions of the invention can, for example, treat various mastitis. As the mastitis, for example, milk and breast are normal, but an increase in somatic cells is observed, and latent mastitis in which significant bacteria are separated, subacute mastitis, acute mastitis, 甚 acute breast These include clinical mastitis in which clinical symptoms such as inflammation are observed, and chronic mastitis in which clinical mastitis has progressed without curing. These mastitis can be treated.
　本発明の組成物の対象は、例えば、特に限定されず、ヒトまたは非ヒト動物を対象とすることができる。本発明の組成物の対象となる非ヒト動物としては、例えば、ウシ、スイギュウ、ヤギ、ヒツジ、ヤク、ウマおよびラクダ等の搾乳動物であり、特に好ましくは乳牛である。前記対象は、例えば、すでに乳房炎を発症した動物でもよいし、乳房炎の発症が確認されていない動物でもよい。 The subject of the composition of the present invention is not particularly limited, for example, and can be a human or non-human animal. The non-human animals to which the composition of the present invention is applied are, for example, milking animals such as cattle, buffalo, goats, sheep, yaks, horses and camels, and particularly preferred are dairy cows. The subject may be, for example, an animal that has already developed mastitis or an animal that has not been confirmed to develop mastitis.
　本発明に用いるオゾン溶存グリセリンの製造方法は、特に制限されず、例えば、グリセリン溶液とオゾンを含む気体とを、気液接触させることで製造することができる。 The method for producing ozone-dissolved glycerin used in the present invention is not particularly limited, and can be produced, for example, by bringing a glycerin solution and a gas containing ozone into gas-liquid contact.
　前記グリセリン溶液は、グリセリンが高濃度であることが好ましい。前記高濃度のグリセリン溶液としては、例えば、グリセリン濃度７５重量％以上のグリセリン溶液を用いることができ、具体例として、日本薬局方品の８４～８７重量％のグリセリン溶液が好ましく、日本薬局方品のグリセリン濃度９８重量％以上の濃グリセリン溶液がより好ましく、濃度９８．５重量％以上の精製グリセリン溶液がさらに好ましい。前記グリセリン溶液は、例えば、グリセリン濃度が相対的に高い程、オゾンをより高濃度に溶存させることができる。前記グリセリン溶液において、グリセリンに対する溶媒は、特に制限されず、例えば、水等の水性溶媒である。 The glycerin solution preferably has a high concentration of glycerin. As the high concentration glycerin solution, for example, a glycerin solution having a glycerin concentration of 75% by weight or more can be used. As a specific example, a 84 to 87% by weight glycerin solution of Japanese Pharmacopoeia product is preferable. A concentrated glycerin solution having a glycerin concentration of 98 wt% or more is more preferable, and a purified glycerin solution having a concentration of 98.5 wt% or more is further preferable. The glycerin solution can dissolve ozone to a higher concentration, for example, as the glycerin concentration is relatively higher. In the glycerin solution, the solvent for glycerin is not particularly limited, and is, for example, an aqueous solvent such as water.
　前記オゾンを含む気体は、オゾンが高濃度であることが好ましい。前記オゾン濃度の高い気体の製造方法は、特に制限されず、例えば、酸素ガスに無声放電することでオゾンを生成するオゾン発生装置を用いて製造することができる。酸素ガスを用いる場合には、例えば、医療用の酸素ボンベを用いてもよいし、また、酸素発生装置で製造された酸素ガスを用いてもよい。 The gas containing ozone preferably has a high concentration of ozone. The method for producing the gas having a high ozone concentration is not particularly limited, and for example, it can be produced using an ozone generator that produces ozone by silent discharge to oxygen gas. When oxygen gas is used, for example, a medical oxygen cylinder may be used, or oxygen gas produced by an oxygen generator may be used.
　前記グリセリン溶液と前記オゾンを含む気体とを気液接触させる方法としては、特に制限されず、例えば、タンクに高濃度（例えば、９８重量％以上）のグリセリン溶液を入れ、散気管を用いて前記タンク内に前記オゾン濃度の高い気体を微細な気泡として放出する方法がある。具体的には、例えば、オゾン濃度８０ｇ／ｋＬ（約３７０００ｐｐｍ）の気体を、前記濃グリセリン溶液中に、約７日間曝気することにより、オゾン濃度約３０００ｐｐｍのオゾン溶存グリセリン溶液を製造することができる。曝気の時間は、特に制限されず、例えば、相対的により長時間行うことにより、オゾン濃度がより高濃度のオゾン溶存グリセリン溶液を製造することができる。 The method for bringing the glycerin solution and the gas containing ozone into gas-liquid contact is not particularly limited. For example, a high concentration (for example, 98% by weight or more) glycerin solution is put in a tank, and There is a method of releasing the gas having a high ozone concentration as a fine bubble in the tank. Specifically, for example, a gas having an ozone concentration of 80 g / kL (about 37000 ppm) may be aerated in the concentrated glycerol solution for about 7 days to produce an ozone-dissolved glycerin solution having an ozone concentration of about 3000 ppm. . The time of aeration is not particularly limited, and, for example, by performing for a relatively longer time, it is possible to produce an ozone-dissolved glycerin solution having a higher ozone concentration.
　本発明に用いるオゾン溶存グリセリンのオゾン濃度は、乳房炎の治療目的に応じて、適宜、調整することができ、特に限定されない。オゾン溶存グリセリンのオゾン濃度は、典型的には、例えば、１ｐｐｍ～１００００ｐｐｍ、１０ｐｐｍ～１００００ｐｐｍであり、好ましくは、１００ｐｐｍ～４０００ｐｐｍである。 The ozone concentration of ozone-dissolved glycerin used in the present invention can be appropriately adjusted depending on the treatment purpose of mastitis, and is not particularly limited. The ozone concentration of the ozone-dissolved glycerin is typically, for example, 1 ppm to 10000 ppm, 10 ppm to 10000 ppm, and preferably 100 ppm to 4000 ppm.
＜治療方法＞
　本発明の乳房炎の治療方法は、前述のように、医薬組成物を乳房内に投与する工程を含み、前記医薬組成物が、前記本発明の乳房炎用医薬組成物である。本発明の治療方法は、前記本発明の組成物を使用することが特徴であって、その他の工程および条件は、何ら制限されない。 <Method of treatment>
The method for treating mastitis of the present invention, as described above, comprises the step of administering a pharmaceutical composition into the breast, and the pharmaceutical composition is the pharmaceutical composition for mastitis of the present invention. The treatment method of the present invention is characterized by using the composition of the present invention, and the other steps and conditions are not limited in any way.
　本発明の治療方法において、前記治療目的は、特に制限されず、前述のように、すでに罹患した対象について、乳房炎の緩和、および治癒を目的としてもよいし、罹患していない対象または罹患の有無が不明な対象について、乳房炎の予防を目的としてもよく、両方であってもよい。すなわち、本発明の治療方法は、例えば、乳房炎を発症した対象に前記組成物を投与する、いわゆる治療でもよいし、乳房炎を発症していない対象に前記組成物を投与する予防でもよいし、乳房炎の発症の有無にかかわらず対象に前記組成物を投与する治療および予防でもよい。 In the treatment method of the present invention, the therapeutic purpose is not particularly limited, and as described above, for the afflicted subject, it may be for the purpose of alleviation and cure of mastitis, and the abjected subject or diseased For subjects whose presence or absence is unknown, it may be for the purpose of preventing mastitis, or both. That is, the treatment method of the present invention may be, for example, so-called treatment in which the composition is administered to a subject who has developed mastitis, or prophylaxis may be performed in which the composition is administered to a subject who has not developed mastitis. The subject may also be treated and prevented by administering the composition to the subject with or without the onset of mastitis.
　本発明の治療方法において、前記組成物の乳房内への投与方法は、特に制限されない。前記投与方法は、例えば、乳房へ注射による注入、乳頭口からカニューレによる注入等によって行われてもよい。例えば、治療対象への侵襲性の低減等の観点から、乳房内への投与は、乳頭口からカニューレによる注入が好ましい。 In the treatment method of the present invention, the method of administering the composition into the breast is not particularly limited. The method of administration may be performed, for example, by injection into the breast by injection, injection through the nipple opening via cannula, etc. For example, from the viewpoint of reducing invasiveness to the treatment subject, intramammary administration is preferably performed by cannula injection from the nipple port.
　本発明の治療方法において、治療対象に対する前記組成物の投与条件は、特に制限されず、前記治療対象の種類、大きさ、治療および予防等の目的、症状の程度等に応じて、適宜決定できる。前記組成物の投与は、例えば、１日あたりの投与回数が、１～２回であり、好ましくは１回である。また、体重にかかわらず、例えば、これまで認可されている乳房炎用注入軟膏と同様に、１ｍｌから１０ｍｌを投与してもよい。 In the treatment method of the present invention, the administration conditions of the composition to the treatment subject are not particularly limited, and can be appropriately determined according to the type, size, purpose of treatment, prevention, etc. of the treatment subject, degree of symptoms, etc. . The administration of the composition is, for example, once or twice, preferably once, per day. Also, regardless of body weight, for example, 1 ml to 10 ml may be administered, as in the previously approved mastitis injection ointment.
＜オゾン溶存グリセリン＞
　本発明のオゾン溶存グリセリンは、前述のように、乳房炎の治療に使用するためのオゾン溶存グリセリンである。本発明のオゾン溶存グリセリンは、前述した本発明の乳房炎医薬組成物および治療方法の記載を援用できる。 <Ozone dissolved glycerin>
The ozone-dissolved glycerin of the present invention is ozone-dissolved glycerin for use in the treatment of mastitis as described above. The ozone-dissolved glycerin of the present invention can be incorporated into the above description of the mastitis pharmaceutical composition and treatment method of the present invention.
　また、本発明のオゾン溶存グリセリンの使用は、乳房炎治療の医薬の製造のためのオゾン溶存グリセリンの使用である。 Also, the use of ozone dissolved glycerin according to the present invention is the use of ozone dissolved glycerin for the manufacture of a medicament for the treatment of mastitis.
　以下、本発明について、さらに詳細に実施例を用いて説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.
［実施例１］オゾン溶存グリセリン（オゾンジェル）の調製
　濃グリセリンとオゾンとを気液接触させ、以下に示すようにして、オゾン溶存グリセリン溶液（オゾンジェル）を製造した。ここで、前記濃グリセリンとは、日本薬局方品の９８重量％以上の濃度のグリセリンを意味する。
　接触槽として、容量５０Ｌのテフロン（登録商標）製タンクを用いた。前記タンクの底面に散気管を設置し、オゾンを微細な気泡として前記タンク内に供給することができるようにした。９０体積％以上の高濃度酸素を含む高濃度酸素気体を原料として、毎時１００ｇのオゾン発生能力を有する無声放電式オゾン発生装置を使用した。 Example 1 Preparation of Ozone-Dissolved Glycerin (Ozone Gel) A concentrated glycerol and ozone were brought into gas-liquid contact, and an ozone-dissolved glycerin solution (ozone gel) was produced as described below. Here, the above-mentioned concentrated glycerin means glycerin having a concentration of 98% by weight or more of the Japanese Pharmacopoeia product.
A 50 L Teflon (registered trademark) tank was used as the contact tank. A diffuser was placed on the bottom of the tank so that ozone could be supplied as fine air bubbles into the tank. Using a high concentration oxygen gas containing high concentration oxygen of 90% by volume or more as a raw material, a silent discharge type ozone generator having an ozone generation capacity of 100 g / hour was used.
　前記タンクに２２ｋｇの前記濃グリセリンを入れ、前記オゾン発生装置に毎分２０Ｌの前記高濃度酸素気体を送り込み、オゾンを含む気体を発生させ、前記発生した気体を、前記散気管から前記タンク内に７日間以上放出し、終濃度４０００ｐｐｍのオゾン濃度のオゾン溶存グリセリン溶液を得た。 22 kg of the concentrated glycerin is put into the tank, and 20 L of the high concentration oxygen gas is sent into the ozone generator to generate a gas containing ozone, and the generated gas is introduced into the tank from the aeration tube The ozone solution was released for 7 days or more, and an ozone dissolved glycerin solution having an ozone concentration of final concentration 4000 ppm was obtained.
［実施例２］オゾン溶存グリセリン（オゾンジェル）の殺菌効果
　実施例１で調製されたオゾン溶存グリセリン（オゾン濃度４０００ｐｐｍ）について、各種の乳房炎の原因菌に対する殺菌効果を、下記方法により確認した。 Example 2 Bactericidal Effect of Ozone-Dissolved Glycerin (Ozone Gel) With respect to the ozone-dissolved glycerin (having an ozone concentration of 4000 ppm) prepared in Example 1, the bactericidal effects against various mastitis-causing bacteria were confirmed by the following method.
　下記表１に示す原因菌を、それぞれ培地に接種し、３７℃で培養し、菌液濃度約３×１０８ＣＦＵ／ｍＬに調整した。前記培地は、前記原因菌の種類に応じて一般的な培地を使用した。前記菌液０．１ｍＬに、前記オゾン溶存グリセリン１ｍＬを加え、室温で均一に混合した。そして、混合開始から、０時間（直後）、３時間後、６時間後に、停止液（６０ｍｇ／ｍＬ　チオ硫酸ナトリウム水溶液）を添加し、菌浮遊液を調製した。前記原因菌ごとに１０倍希釈系列を調製し、原因菌に対する前記培地を用いた平板培養法により、３７℃で培養を行った。そして、培養後に増殖した集落数（ＣＦＵ）を測定し、１ｍＬあたりの生菌数を算出した（検出限界１．０×１０２ＣＦＵ／ｍＬ）。また、ブランクとして、前記オゾン溶存グリセリンに代えて、９８％グリセリン１ｍＬを添加して、同様に培養を行い、生菌数を算出した。これらの結果を表１に示す。 The cause bacteria shown in Table 1 below were each inoculated into a culture medium, cultured at 37 ° C., and adjusted to a culture solution concentration of about 3 × 10 8 CFU / mL. The medium used was a general medium according to the type of the pathogen. To 0.1 mL of the bacterial solution, 1 mL of the ozone-dissolved glycerin was added and uniformly mixed at room temperature. Then, a stop solution (60 mg / mL aqueous sodium thiosulfate solution) was added for 0 hour (immediately after), 3 hours after, and 6 hours after the start of mixing, to prepare a bacterial suspension. A 10-fold dilution series was prepared for each of the causative bacteria, and culture was performed at 37 ° C. by a plate culture method using the medium for the causative bacteria. Then, the number of colonies (CFU) grown after culture was measured, and the number of viable cells per 1 mL was calculated (detection limit: 1.0 × 10 2 CFU / mL). As a blank, 1 mL of 98% glycerin was added in place of the ozone-dissolved glycerin, and culture was similarly performed to calculate the viable cell count. The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　前記表１に示すとおり、前記オゾン溶存グリセリンは、乳房炎の代表的な原因菌である黄色ブドウ球菌（Staphylococcus aureus）および表皮ブドウ球菌（Staphylococcus epidermidis）のいずれのブドウ球菌に対しても、強く継続的な殺菌効果を示した。また、メチシリン耐性黄色ブドウ球菌（Methicillin-Resistant Staphylococcus aureus (MRSA)）に対しても強く継続的な殺菌効果を示しており、耐性菌に対する十分な殺菌効果を示した。さらに、前記オゾン溶存グリセリンは、急性乳房炎等の原因菌である大腸菌（Escherichia coli）および肺炎桿菌（Klebsiella pneumoniae）に対して、強く継続的な殺菌効果を示した。 As shown in Table 1 above, the above ozone-dissolved glycerin is strongly continued against any staphylococci of Staphylococcus aureus that are representative causes of mastitis and Staphylococcus epidermidis. Showed an effective bactericidal effect. In addition, it shows strong and continuous bactericidal effect against methicillin resistant Staphylococcus aureus (Methicillin-Resistant Staphylococcus aureus (MRSA)) and shows sufficient bactericidal effect against resistant bacteria. Furthermore, the above-mentioned ozone dissolved glycerin showed a strong and continuous bactericidal effect against Escherichia coli (Escherichia coli) and Klebsiella pneumoniae, which are causative bacteria such as acute mastitis.
　また、前記オゾン溶存グリセリンは、乳房炎の原因となることが知られている、緑膿菌（Pseudomonas aeruginosa）およびカンジダ・アルビカンス（Candida albicans）に対して強く継続的な殺菌効果を示した。したがって、本発明におけるオゾン溶存グリセリンは、種々の乳房炎に対して広く効果的に予防効果および／または治療効果を奏することが示された。 In addition, the above-mentioned ozone dissolved glycerin showed a strong and continuous bactericidal effect against Pseudomonas aeruginosa and Candida albicans which are known to cause mastitis. Therefore, it was shown that ozone dissolved glycerin in the present invention exerts a preventive effect and / or a therapeutic effect widely and effectively against various mastitis.
［実施例３］慢性乳房炎へのオゾン溶存グリセリンの投与
　実施例１で調製されたオゾン溶存グリセリンを用い、慢性乳房炎を発症した乳牛に対して投与実験を行った。前記オゾン溶存グリセリンは、オゾン濃度４０００ｐｐｍと１０００ｐｐｍとを使用した。オゾン濃度１０００ｐｐｍのオゾン溶存グリセリンは、前記実施例１で調製した４０００ｐｐｍのオゾン溶存グリセリンを、生理的食塩水で希釈した調製した。乳牛への投与は、ミルクカニューレを用いて、乳頭口から乳房内へ投与した。投与は、１日１回とした。そして、投与開始日と最終観察日に、乳汁を採取し、それぞれの乳汁について、前記乳汁中に含まれる菌種を同定し、体細胞数（白血球、乳腺上皮細胞等の細胞の総数、万個／ｍＬ）を測定した。また、治療効果の有無（有効性の有無）については、体細胞数の結果を含め、臨床的に獣医師によって判断された。なお、体細胞数は、５０万個／ｍＬ以下であれば、乳房炎への影響がないと判断し、最終的に臨床症状が治癒し、且つ、乳汁を合乳することでその合乳における体細胞数が３０万個以下であれば出荷可能という点も加味し、獣医師が治癒判断を行った。 Example 3 Administration of Ozone-Dissolved Glycerin to Chronic Mastitis Using the ozone-dissolved glycerin prepared in Example 1, a dose experiment was conducted on a cow suffering from chronic mastitis. The ozone dissolved glycerin used ozone concentrations of 4000 ppm and 1000 ppm. The ozone-dissolved glycerol having an ozone concentration of 1000 ppm was prepared by diluting 4000 ppm of the ozone-dissolved glycerol prepared in Example 1 with physiological saline. Administration to dairy cows was administered intra-mammary from the nipple port using a milk cannula. Administration was once a day. Then, milk is collected on the day of administration start and on the final observation day, and the bacterial species contained in the milk is identified for each milk, and the number of somatic cells (total number of cells such as white blood cells, mammary epithelial cells, etc., 10,000) / ML) was measured. In addition, the veterinarian clinically judged the presence or absence of the treatment effect (presence or absence of efficacy), including the results of the number of somatic cells. In addition, if the number of somatic cells is 500,000 cells / mL or less, it is judged that there is no influence on mastitis, and the clinical symptoms are finally cured, and the milk is added to the milk to formulate it. If the number of somatic cells is less than 300,000, the veterinarian made a judgment on healing, taking into consideration that shipping is possible.
＜投与例１＞
　前記オゾン溶存グリセリン（オゾン濃度１０００ｐｐｍ）５ｍｌを生理的食塩水４５ｍｌにて１０倍希釈し、この希釈液総量５０ｍＬを１４日間、前記乳牛３個体に投与した（症例１～２）。これらの結果を表２に示す。下記表２において、有効性は、獣医師による治療効果の有無の結果であり、〇が、治療効果あり、×が、治療効果無しの判断である（後述する表においても同様）。表２に示すとおり、前記オゾン溶存グリセリンを長期投与した結果、原因となる細菌数が著しく減少し、前記オゾン溶存グリセリンが有効であることが確認された。 <Example 1 of administration>
Five ml of the ozone-dissolved glycerin (ozone concentration: 1000 ppm) was diluted 10-fold with 45 ml of physiological saline, and 50 ml of the total amount of the diluted solution was administered to the three cows for 14 days (cases 1 and 2). The results are shown in Table 2. In Table 2 below, effectiveness is the result of the presence or absence of the treatment effect by the veterinarian, and 〇 is the judgment of treatment effect, and × is the judgment of no treatment effect (the same applies to the table described later). As shown in Table 2, as a result of long-term administration of the ozone-dissolved glycerin, the number of bacteria causing them was significantly reduced, and it was confirmed that the ozone-dissolved glycerin was effective.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
＜投与例２＞
　前記オゾン溶存グリセリン（オゾン濃度４０００ｐｐｍ）５ｍｌを生理的食塩水４５ｍｌにて１０倍希釈し、この希釈液総量５０ｍＬを短期または長期で投与した（症例４および５）。これらの結果を表３に示す。表３に示すとおり、前記オゾン溶存グリセリンを長期投与または短期投与した結果、原因となる細菌数が著しく減少し、前記オゾン溶存グリセリンが有効であることが確認された。 <Example 2 of administration>
Five ml of the ozone-dissolved glycerin (ozone concentration: 4,000 ppm) was diluted 10-fold with 45 ml of physiological saline, and 50 ml of the total amount of the diluted solution was administered in a short or long term (cases 4 and 5). The results are shown in Table 3. As shown in Table 3, as a result of long-term administration or short-term administration of the ozone-dissolved glycerin, the number of bacteria causing them was significantly reduced, and it was confirmed that the ozone-dissolved glycerin was effective.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
＜投与例３＞
　前記オゾン溶存グリセリン（オゾン濃度１０００ｐｐｍ）５ｍｌをそのまま乳房内へ投与した（症例６）。この結果を表４に示す。表４に示すとおり、前記オゾン溶存グリセリンを希釈せずに原液をそのまま注入しても、細菌数が著しく減少し有効であることが確認された。 <Example 3 of administration>
5 ml of the ozone-dissolved glycerin (1000 ppm ozone concentration) was directly administered into the breast (case 6). The results are shown in Table 4. As shown in Table 4, even when the stock solution was injected as it was without diluting the ozone-dissolved glycerin, the number of bacteria was significantly reduced and it was confirmed to be effective.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
＜投与例４＞
　前記オゾン溶存グリセリン（オゾン濃度４０００ｐｐｍ）５ｍｌをそのまま乳房内へ投与した（症例７～２１）。これらの結果を表５に示す。表５に示すとおり、１５症例中１３症例で有効であり、有効率８６．６％であった。本実施例における投与対象は、慢性乳房炎の乳牛であり、慢性乳房炎は、耐性により抗生物質が無効になったことで慢性化している。したがって、慢性乳房炎の乳牛に対して、このような極めて高い有効率を示すということは、耐性菌の影響を受けることなく、効果的に慢性乳房炎を治療できることを意味する。 <Example 4 of administration>
5 ml of the ozone-dissolved glycerin (ozone concentration 4000 ppm) was directly administered into the breast (cases 7 to 21). These results are shown in Table 5. As shown in Table 5, it was effective in 13 of 15 cases, and the efficacy rate was 86.6%. The administration subject in this example is a cow with chronic mastitis, and chronic mastitis is made chronic by the fact that the antibiotic has become ineffective due to resistance. Therefore, showing such an extremely high efficacy rate for dairy cows with chronic mastitis means that chronic mastitis can be treated effectively without being affected by resistant bacteria.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　このように、本発明の組成物の投与によって、体細胞数が減少したことにより、出荷可能な乳量が増加し、乳房炎による乳量損失を低減することができた。また、前記組成物の投与による、乳牛への悪影響は見られなかった。 Thus, administration of the composition of the present invention increased the amount of milk that can be shipped by reducing the number of somatic cells, and was able to reduce the loss of milk due to mastitis. In addition, no adverse effect was observed on dairy cows by the administration of the composition.
　慢性乳房炎は、臨床性乳房炎が治癒せずに進行したものであり、これまで抗生物質の投与などを試みても治療できなかった例も含まれる。本発明の組成物の投与によって、慢性乳房炎を極めて高い有効率で治療できたことは、極めて優れた結果である。 Chronic mastitis is an advanced form of clinical mastitis that has not been cured, and some cases have not been treated even if antibiotics have been tried. The ability to treat chronic mastitis with a very high efficacy rate by administration of the composition of the present invention is a very good result.
　以上、実施形態を参照して本発明を説明したが、本発明は、上記実施形態に限定されるものではない。本発明の構成や詳細には、本発明のスコープ内で当業者が理解しうる様々な変更をできる。 Although the present invention has been described above with reference to the embodiments, the present invention is not limited to the above embodiments. The configurations and details of the present invention can be modified in various ways that can be understood by those skilled in the art within the scope of the present invention.
　この出願は、２０１７年１１月１６日に出願された日本出願特願２０１７－２２０７７５を基礎とする優先権を主張し、その開示のすべてをここに取り込む。 This application claims priority based on Japanese Patent Application No. 2017-220775 filed on Nov. 16, 2017, the entire disclosure of which is incorporated herein.
　本発明の乳房炎用医薬組成物は、例えば、ヒト用または非ヒト動物用として用いることができる。特に乳牛等の搾乳動物の乳房炎を治療でき、ヒトに対する医薬のみならず、動物に対する医薬としても有用である。

  The pharmaceutical composition for mastitis of the present invention can be used, for example, for human or non-human animals. In particular, it can treat mastitis of milking animals such as dairy cows, and is useful not only as medicine for humans but also as medicine for animals.

Claims (14)

  1. オゾン溶存グリセリンを含む、乳房炎用医薬組成物。 A pharmaceutical composition for mastitis, comprising ozone-dissolved glycerin.
  2. グリセリン以外の希釈物質をさらに含む、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, further comprising a diluent other than glycerin.
  3. 前記希釈物質が、水性溶媒である、請求項２記載の医薬組成物。 The pharmaceutical composition of claim 2, wherein the diluent is an aqueous solvent.
  4. 前記水性溶媒が、水または生理的食塩水である、請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the aqueous solvent is water or saline.
  5. 有効成分として、前記オゾン溶存グリセリンを含む、請求項１から３のいずれか一項に記載の乳房炎用医薬組成物。 The pharmaceutical composition for mastitis according to any one of claims 1 to 3, wherein the ozone-dissolved glycerin is contained as an active ingredient.
  6. 前記乳房炎が、慢性乳房炎である、請求項１から５のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the mastitis is chronic mastitis.
  7. 搾乳動物用の医薬組成物である、請求項１から６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, which is a pharmaceutical composition for a milking animal.
  8. 前記搾乳動物が、乳牛である、請求項６に記載の医薬組成物。 The pharmaceutical composition according to claim 6, wherein the milking animal is a dairy cow.
  9. 医薬組成物を乳房内に投与する投与工程を含み、
    前記医薬組成物が、請求項１から８のいずれか一項に記載の乳房炎用医薬組成物である、乳房炎の治療方法。     Including the administration step of intramammary administration of the pharmaceutical composition,
    A method for treating mastitis, wherein the pharmaceutical composition is a pharmaceutical composition for mastitis according to any one of claims 1 to 8.
  10. 　前記投与工程において、乳頭口から、カニューレによって前記医薬組成物を注入する、請求項９に記載の方法。 The method according to claim 9, wherein in the administration step, the pharmaceutical composition is injected through a nipple via a cannula.
  11. 投与対象の動物が、非ヒト動物である、請求項９または１０記載の方法。 The method according to claim 9 or 10, wherein the animal to be administered is a non-human animal.
  12. 前記非ヒト動物が、搾乳動物である、請求項１１に記載の方法。 The method according to claim 11, wherein the non-human animal is a milking animal.
  13. 前記搾乳動物が、乳牛である、請求項１２に記載の方法。 The method according to claim 12, wherein the milking animal is a dairy cow.
  14. 乳房炎の治療に使用するためのオゾン溶存グリセリン。

          Ozone-dissolved glycerin for use in the treatment of mastitis.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022239651A1 (en) * 2021-05-10 2022-11-17 株式会社メディプラス製薬 Antiviral composition and use thereof
WO2023057989A3 (en) * 2021-10-07 2023-08-03 Roberto Albertelli A method and an apparatus for making a treatment solution and for providing said treatment solution to a biological system

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0677709U (en) * 1993-04-27 1994-11-01 日本全薬工業株式会社 Mastitis therapeutic agent injection aid for dairy cows
KR20010100340A (en) * 2000-05-01 2001-11-14 깁수경 Oil-based topical preparation including ozone, method of preparation and generator thereof
JP2005232094A (en) * 2004-02-20 2005-09-02 Vmc Co Ltd Ozone dissolved glycerol solution, ozone dissolved glycerol solidified material and ozone dissolved mixed solution, method for producing ozone dissolved glycerol solution, method for producing ozone dissolved mixed solution and method for preserving ozone dissolved glycerol solution

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0677709U (en) * 1993-04-27 1994-11-01 日本全薬工業株式会社 Mastitis therapeutic agent injection aid for dairy cows
KR20010100340A (en) * 2000-05-01 2001-11-14 깁수경 Oil-based topical preparation including ozone, method of preparation and generator thereof
JP2005232094A (en) * 2004-02-20 2005-09-02 Vmc Co Ltd Ozone dissolved glycerol solution, ozone dissolved glycerol solidified material and ozone dissolved mixed solution, method for producing ozone dissolved glycerol solution, method for producing ozone dissolved mixed solution and method for preserving ozone dissolved glycerol solution

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022239651A1 (en) * 2021-05-10 2022-11-17 株式会社メディプラス製薬 Antiviral composition and use thereof
WO2023057989A3 (en) * 2021-10-07 2023-08-03 Roberto Albertelli A method and an apparatus for making a treatment solution and for providing said treatment solution to a biological system

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