WO2021261599A1 - Agent prophylactique/thérapeutique pour une nouvelle maladie infectieuse à coronavirus - Google Patents

Agent prophylactique/thérapeutique pour une nouvelle maladie infectieuse à coronavirus Download PDF

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Publication number
WO2021261599A1
WO2021261599A1 PCT/JP2021/024257 JP2021024257W WO2021261599A1 WO 2021261599 A1 WO2021261599 A1 WO 2021261599A1 JP 2021024257 W JP2021024257 W JP 2021024257W WO 2021261599 A1 WO2021261599 A1 WO 2021261599A1
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WIPO (PCT)
Prior art keywords
vitamin
therapeutic agent
riboflavin
leucoflavin
infectious disease
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PCT/JP2021/024257
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English (en)
Japanese (ja)
Inventor
誠一 荒木
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誠一 荒木
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Publication of WO2021261599A1 publication Critical patent/WO2021261599A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to a new type coronavirus infectious disease preventive / therapeutic agent containing vitamin B2.
  • the new coronavirus infection is an infection caused by "SARS-CoV2" (hereinafter referred to as "new coronavirus"), and WHO names the infection caused by this new coronavirus "COVID-19".
  • Symptoms of the new coronavirus infection include fever (37.5 ° C or higher), sore throat, cough, sputum and other cold-like symptoms, and olfactory and taste disorders may occur, including 4 days or more. After the course, high fever, chest discomfort, dyspnea, etc. may appear, and if it becomes severe, it may progress to pneumonia. Inflammation may occur not only in pneumonia but also in other respiratory organs such as upper respiratory tract inflammation and bronchitis.
  • Cytokine storm there is systemic inflammation called "cytokine storm” as a characteristic when it becomes severe. Cytokine storms may cause inflammation of blood vessels throughout the body, and in severe cases, complications such as thrombosis have also been observed. It has also been reported that a direct attack on blood vessels by the new coronavirus also causes thrombosis.
  • the therapeutic agents (silver bullets), preventive agents, vaccines, etc. for this new type of coronawill infection have not been sufficiently developed at present, and it is desired to develop effective preventive / therapeutic agents as soon as possible.
  • Patent Document 1 “immunostimulatory / infection protective agent and method for producing the same” in Patent Document 1 and "pharmaceutical containing a vitamin B2 reductant” in Patent Document 2, which are composed of riboflavin and / or a riboflavin derivative as vitamin B2 drugs.
  • Patent Document 3 “Method for producing reduced vitamin B2 and its preparation” in Patent Document 3
  • Patent Document 4 “Pharmaceuticals containing riboflavin-based compounds” in Patent Document 4 have been developed and published.
  • Patent Document 2 for example, immunity containing leucoflavin, monohydroflavin, leucoflavin phosphate ester, leucoflavin mononucleotide, leucoflavin adenindinucleotide, or a pharmacologically acceptable salt thereof as an active ingredient.
  • an activation / infection protective therapeutic agent claim 1
  • a septicemia preventive therapeutic agent a septic shock preventive therapeutic agent
  • a malaria preventive therapeutic agent for example, uses as an activation / infection protective therapeutic agent (claim 1), a septicemia preventive therapeutic agent, a septic shock preventive therapeutic agent, and a malaria preventive therapeutic agent.
  • the reduced vitamin B2 was oxidized and returned to the vitamin B2, and the state of the reduced vitamin B2 could not be stably maintained.
  • Patent Document 2 states that "the riboflavin-reduced agent and / or the reduced agent of the riboflavin derivative in the present invention, or a pharmaceutically acceptable salt thereof is a commonly used hydrosulfite. Alternatively, it can be easily produced by adding a reducing agent such as tin chloride. ”As a reducing agent that cannot be used on the human body is used, the reducing agent is removed during treatment and administration to the human body. It has not been put into practical use in terms of cost and side effects.
  • Patent Document 3 a preparation containing reduced vitamin B2, which can be easily produced at low cost, can be stably stored and distributed for a long period of time, and can be safely administered. It also offers new uses for reduced vitamin B2 that has not been used. Specifically, a reduced vitamin B2 preparation for vascular endothelial cell protection recovery caused by mitochondrial activation, which comprises hydrogen water and reduced vitamin B2 dissolved in the hydrogen water, and at the same time, the present invention is active.
  • It also acts as an oxygen scavenger, an oxidative stress scavenger, an excess cytokine suppressant, a fatigue recovery agent, a blood cell count recovery agent, a hepatic / renal disorder recovery agent, and a preventive or therapeutic agent for cancer diseases or dementia.
  • vitamin B2 has an excellent cytokine-suppressing effect and acts as a prophylactic or therapeutic agent for inflammatory diseases associated with hypercytokine storms.
  • Immunity includes innate immunity and acquired immunity. In innate immunity, neutrophils, macrophages, NK cells, etc. first non-specifically eliminate pathogens that have invaded the body or destroy infected cells. Acquired immunity, on the other hand, is eliminated by specific antibodies to the pathogen, or in collaboration with cell-mediated immunity, which vaccines utilize.
  • the present invention provides a new type coronavirus infectious disease preventive / therapeutic agent containing vitamin B2.
  • a new type of coronavirus infection preventive / therapeutic agent characterized by containing vitamin B2
  • the new coronavirus infection preventive / therapeutic agent according to (1) which is one or more selected from those chlorides.
  • Vitamin B2 The new coronavirus according to (1) or (2), which is in the form of any one selected from injections, tablets, granules, powders, capsules, inhalants, troches and drinks. Infectious disease prevention / therapeutic agent. It was made into the composition of.
  • vitamin B2 is another name for riboflavin and its derivatives, and is a substance naturally contained in liver, beer yeast, milk, meat, eggs, green vegetables and the like.
  • As a drug it is used as a preventive and therapeutic agent for diseases such as angular cheilitis, cheilitis, glossitis, sudden / chronic eczema, seborrheic eczema, and pellagra.
  • Vitamin B2 exists in the bound form in vivo, that is, in the form of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), and functions as a prosthetic group of oxidoreductase called flavin protein or flavin enzyme. It plays a central role in the oxidative degradation of lipids and amino acids and the electron transfer of mitochondria and microsomes.
  • FMN flavin mononucleotide
  • FAD flavin adenine dinucleotide
  • the dose of vitamin B2 as an injectable drug is 0.1 mg to 100 mg, preferably 0.5 mg to 50 mg, and more preferably 1 mg to 25 mg per 1 kg of body weight.
  • the method of administering vitamin B2 is not particularly limited, but it is preferable to administer it as an injection or an inhaler in the case of severe shock. If the symptoms are mild, it can be administered orally or via the rectum.
  • the daily dose as an oral preparation is 30 mg to 500 mg, preferably 50 mg to 400 mg, and more preferably 70 mg to 360 mg.
  • Vitamin B2 has been known to enhance innate immunity as an immunostimulator, which eliminates pathogens and has been shown to be effective against hypercytokine storms caused by endotoxic shock. It is also expected to be effective against cytokine storms in new coronavirus infections.
  • cytokine storm means that cytokines, which are originally directed to eliminate pathogens, are overproduced, runaway, become hypercytokineemia, and become a state of cytokine storm. In this state, even normal cells are damaged, causing organ failure and ultimately death.
  • Vitamin B2 is inexpensive, can be supplied in large quantities, is highly versatile and highly safe in the world including emerging countries, and is an epoch-making therapeutic drug or preventive drug as an oral administration drug or an injection drug. It can be one of the medicines. Indeed, vitamin B2 as a selective invention can be said to be an epoch-making preventive / therapeutic agent for a new type of coronavirus that has never existed and has newly occurred.
  • a pig pseudorabies virus (Pseudorabies virus) was used, and 133PFU was subcutaneously inoculated into mice, and the survival rate thereafter was measured based on animal ethics.
  • mice ICR male mice were used as mice, and the number of mice was 10 per group.
  • Riboflavin sodium phosphate was used as vitamin B2, dissolved in distilled water for injection, and then sterilized and filtered through a 0.22 ⁇ m filter to obtain a 5 w / v% injection solution (hereinafter referred to as this sample). Distilled water for injection was used as a control sample.
  • Vitamin B2 was injected intravenously three times immediately after infection with Oeski virus, one or two days later, and the therapeutic effect was observed. The effects were statistically compared by the ⁇ 2 test. The results are shown in Table 1.
  • vitamin B2 is known to prevent endotoxin-induced hypercytokineemia (Patent Document 4), and is considered to have the same mechanism of action, and is sufficiently resistant to cytokine storms caused by the new coronavirus. Expected to be useful.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Le problème à résoudre par la présente invention est de fournir un agent prophylactique/thérapeutique pour une nouvelle maladie infectieuse à coronavirus, l'agent contenant de la vitamine B2. La solution selon la présente invention porte sur un agent prophylactique/thérapeutique pour une nouvelle maladie infectieuse à coronavirus, l'agent étant caractérisé en ce qu'il contient de la vitamine B2, et plus précisément, caractérisé en ce que la vitamine B2 est un ou plusieurs constituants choisis dans le groupe constitué par : la riboflavine ; le phosphate sodique de riboflavine (ester de phosphate sodique de riboflavine) ; un ester de butyrate de riboflavine ; la flavine mononucléotide et la flavine adénine dinucléotide ; la leucoflavine ; la monohydroflavine ; un ester de phosphate de leucoflavine ; la leucoflavine mononucléotide ; la leucoflavine adénine dinucléotide ; et leurs chlorures.
PCT/JP2021/024257 2020-06-26 2021-06-25 Agent prophylactique/thérapeutique pour une nouvelle maladie infectieuse à coronavirus WO2021261599A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020-110973 2020-06-26
JP2020110973A JP2022007796A (ja) 2020-06-26 2020-06-26 新型コロナウイルス感染症予防・治療剤

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995033483A1 (fr) * 1994-06-07 1995-12-14 Toray Industries, Inc. Agent preventif et curatif contre les maladies provoquees par la formation de fibrinoides ou de thrombus dans les poumons et modele animal pour ces maladies
WO2003075935A1 (fr) * 2002-03-11 2003-09-18 Eisai Co., Ltd. Medicaments contenant des composes du type riboflavine
JP2004345988A (ja) * 2003-05-21 2004-12-09 Eisai Co Ltd リボフラビン系化合物を含む医薬組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995033483A1 (fr) * 1994-06-07 1995-12-14 Toray Industries, Inc. Agent preventif et curatif contre les maladies provoquees par la formation de fibrinoides ou de thrombus dans les poumons et modele animal pour ces maladies
WO2003075935A1 (fr) * 2002-03-11 2003-09-18 Eisai Co., Ltd. Medicaments contenant des composes du type riboflavine
JP2004345988A (ja) * 2003-05-21 2004-12-09 Eisai Co Ltd リボフラビン系化合物を含む医薬組成物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KITAJIMA HEITA, ET AL.: "Report of 9 cases of severe COVID-19 pneumonia using tocilizumab (Actemra)", JAPANESE SOCIETY OF INFECTIOUS DISEASES CASE REPORT, 30 April 2020 (2020-04-30), pages 1 - 6, XP055893626, Retrieved from the Internet <URL:https://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_casereport_200430_2.pdf> [retrieved on 20220221] *
NIITSU, YOSHIFUMI: "Effect of IL -6 on coagulation and fibrinolytic activity of vascular endothelial cells", vol. 4, no. 6, 1993, pages 409 - 416 *
XIAOLING XU, HAN MINGFENG, LI TIANTIAN, SUN WEI, WANG DONGSHENG, FU BINQING, ZHOU YONGGANG, ZHENG XIAOHU, YANG YUN, LI XIUYONG, ZH: "Effective treatment of severe COVID-19 patients with tocilizumab", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 117, no. 20, 29 April 2020 (2020-04-29), pages 10970 - 10975, XP055740697, ISSN: 0027-8424, DOI: 10.1073/pnas.2005615117 *

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