WO2023068287A1 - Novel pharmaceutical - Google Patents

Novel pharmaceutical Download PDF

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Publication number
WO2023068287A1
WO2023068287A1 PCT/JP2022/038872 JP2022038872W WO2023068287A1 WO 2023068287 A1 WO2023068287 A1 WO 2023068287A1 JP 2022038872 W JP2022038872 W JP 2022038872W WO 2023068287 A1 WO2023068287 A1 WO 2023068287A1
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Prior art keywords
ivermectin
molnupiravir
covid
cov
sars
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PCT/JP2022/038872
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French (fr)
Japanese (ja)
Inventor
浩一 白石
睦男 奥村
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興和株式会社
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Publication of WO2023068287A1 publication Critical patent/WO2023068287A1/en

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    • 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
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/7068—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 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to preventive and/or therapeutic agents for diseases based on SARS-CoV-2 infection.
  • COVID-19 Japanese name: novel coronavirus infectious disease
  • SARS-CoV-2 2019 novel coronavirus
  • COVID-19 is an infectious disease that was confirmed to occur in Wuhan, People's Republic of China in November 2019 and was reported to WHO in December of the same year, and has spread worldwide since then.
  • Symptoms include fever, dry cough, fatigue, sputum production, shortness of breath, sore throat, headache, muscle pain, joint pain, dysosmia, and dysgeusia. is taken.
  • there are still unknown points such as its infectivity and the rate of severe disease when contracted, and because it is a new type, effective treatment methods are still being sought, causing anxiety around the world.
  • Non-Patent Document 1 ivermectin is expected as a therapeutic drug for COVID-19, a disease based on SARS-CoV-2 infection.
  • Molnupiravir is known to exhibit antiviral effects by causing replication errors during viral RNA replication, and is expected to be a therapeutic drug for COVID-19, a disease caused by SARS-CoV-2 infection.
  • An object of the present invention is to provide a new drug for the prevention and/or treatment of COVID-19, a disease based on SARS-CoV-2 infection.
  • it is intended to provide a medicament for the prevention and/or treatment of mild or moderate COVID-19.
  • Ivermectin has already been used in Japan as a treatment for intestinal strongyloidiasis and scabies in tablet form. It is also expected as an orally administrable drug for treatment.
  • Molnupiravir exhibits antiviral activity, it is expected as an orally administrable therapeutic agent for COVID-19, a disease based on SARS-CoV-2 infection.
  • the inventors have focused on combining ivermectin and mornupiravir for the suppression of CoV-2 infection or the prevention and/or treatment of COVID-19, leading to the present invention.
  • the present invention provides the following inventions [1] to [9].
  • a pharmaceutical comprising a combination of ivermectin and mornupiravir.
  • a prophylactic and/or therapeutic agent for SARS-CoV-2 infection which is a combination of ivermectin and molnupiravir.
  • a preventive and/or therapeutic agent for COVID-19 which is a combination of ivermectin and molnupiravir.
  • Use of ivermectin and molnupiravir for prophylactic and/or therapeutic drug production for SARS-CoV-2 infection.
  • a method for preventing and/or treating COVID-19 which comprises administering ivermectin and molnupiravir.
  • the medicament obtained by combining ivermectin and molnupiravir of the present invention is effective in suppressing SARS-CoV-2 infection or preventing and / or treating COVID-19, that is, symptoms of COVID-19 (fever, cough, Shortness of breath, muscle pain, nasal discharge, sore throat, headache, nausea, vomiting, abdominal pain, diarrhea, dysosmia, dysgeusia) are improved or eliminated.
  • both ivermectin and molnupiravir are drugs that exert their effects when administered orally. It is possible to prescribe and administer drugs at any clinic.
  • the mechanism of antiviral action of ivermectin and the mechanism of antiviral action of mornupiravir are different, it is expected that the antiviral action will be enhanced by their combined use.
  • the medicament obtained by combining ivermectin and molnupiravir of the present invention is effective in suppressing SARS-CoV-2 infection or preventing and/or treating COVID-19.
  • the ivermectin used in the present invention may contain at least either ivermectin B1a or ivermectin B1b as ivermectin.
  • a mixture containing both ivermectin B1a and ivermectin B1b is preferable, and 90% or more of ivermectin B1a and ivermectin Mixtures containing less than 10% B 1b are more preferred.
  • ivermectin is a known chemical substance, and can be obtained by purchasing a commercial product or by producing avermectin by selective catalytic hydrogenation followed by removal of the catalyst.
  • the administration route of the ivermectin-containing medicament of the present invention is not particularly limited, and may be oral administration or parenteral administration.
  • a drug containing ivermectin When a drug containing ivermectin is administered orally, the dosage varies depending on the patient's body weight, age, sex, symptoms, etc., but the usual dose for adults is 0.1 to 1 mg/kg body weight per day as ivermectin. 0.15 to 0.5 mg/kg body weight, more preferably 0.2 to 0.4 mg/kg body weight. Assuming that the body weight of an adult is 60 kg, the daily dose is usually 6 to 60 mg, preferably 12 to 24 mg. The daily dose can be divided and administered about 1 to 4 times.
  • oral administration formulations examples include capsules, pills, granules, fine granules, powders, tablets, liquid formulations, syrups, jellies, lozenges, etc.
  • Oral administration formulations containing these ivermectins are known. It can be manufactured by the method of As the dosage form of oral administration preparations, solid preparations are preferable, and capsules, pills, granules, fine granules, powders, and tablets are particularly preferable.
  • the ivermectin content per dosage unit of these oral administration preparations is preferably 3 mg and 6 mg in consideration of the dosage amount.
  • a tablet containing 3 mg of ivermectin is on the market, and if ivermectin is approved for the suppression of SARS-CoV-2 infection or the prevention and / or treatment of COVID-19, it should be used. can also be possible.
  • molnupiravir has the IUPAC name ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H) -yl) tetrahydrofuran-2-yl) methyl isobutylate, which is a known chemical substance, can be obtained by purchasing a commercially available product or by producing it by a known method.
  • the administration route of the medicament containing molnupiravir of the present invention is not particularly limited, and may be oral administration or parenteral administration.
  • a drug containing molnupiravir is administered orally, the dosage varies depending on the patient's body weight, age, sex, symptoms, etc., but the usual daily dose of molnupiravir for adults is 10 to 5000 mg. Well, it is preferably 100-3200 mg, more preferably 200-1600 mg.
  • the daily dose can be divided and administered about 1 to 4 times.
  • oral administration formulations examples include capsules, pills, granules, fine granules, powders, tablets, liquid formulations, syrups, jellies, lozenges, etc.
  • Oral administration formulations containing these molnupiravir are known. It can be manufactured by the method of As the dosage form of oral administration preparations, solid preparations are preferable, and capsules, pills, granules, fine granules, powders, and tablets are particularly preferable.
  • the content of molnupiravir per dosage unit of these oral administration preparations is preferably 100 mg and 200 mg in consideration of the dosage amount.
  • a dosage form such as an inhalant that can be directly applied to the lower respiratory tract as a site of SARS-CoV-2 infection can be administered unlike an injection. is convenient, it can be cited as a preferred dosage form among parenteral administration.
  • the particle size is preferably 0.5 to 10 ⁇ m from the viewpoint of accessibility to the lower respiratory tract. 0.5 to 8 ⁇ m, more preferably 0.5 to 6 ⁇ m.
  • the mass median aerodynamic diameter of ivermectin and molnupiravir is preferably 0.5 to 10 ⁇ m, more preferably 0.5 to 8 ⁇ m, and more preferably 0.5 to 6 ⁇ m. is more preferred.
  • the particle size of ivermectin and molnupiravir is the particle size of the ivermectin-containing powder or molnupiravir-containing powder in the case of a powder, and the particle size of the ivermectin-containing atomized droplets or molnupiravir-containing atomized droplets in the case of a liquid formulation.
  • the particle size can be adjusted by pulverization, sieving, etc. during powder production.
  • inhalants include inhalation powders, inhalation liquids, and inhalation aerosols, but are not particularly limited.
  • a suitable device or device for administration by inhalation may be used, or a container combined with a device for inhalation may be filled.
  • the inhalable powder preparation is a preparation for inhalation as an aerosol of ivermectin-containing powder or molnupiravir-containing powder prepared so that the inhalation amount is constant. More preferably, it may be prepared as a powder having a particle size of 0.5 to 8 ⁇ m, more preferably 0.5 to 6 ⁇ m, specifically, preferably 0.5 to 10 ⁇ m, more preferably 0.5 to 8 ⁇ m. and more preferably as a powder having a mass median aerodynamic diameter of 0.5 to 6 ⁇ m.
  • Sugar or sugar alcohol can be used as an additive for the ivermectin-containing powder or molnupiravir-containing powder.
  • sugars include lactose hydrate, sucrose, and glucose
  • sugar alcohols include erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol.
  • ivermectin-containing powder a freeze-dried product containing ivermectin and a lactic acid/glycolic acid copolymer described in JP-A-2019-69906 can also be mentioned.
  • DPI dry powder inhaler
  • Devices commonly used as DPIs can be used for the inhalable powder formulation of the present invention.
  • devices using capsules include Monohaler, Handyhaler, Breezhaler, Flowcaps and the like.
  • Other examples include Dischaler, Discus, and Ellipta, which use aluminum blisters.
  • Turbuhaler, Crickhaler, Swinghaler, Twisthaler and the like are examples of reservoir-type devices in which a powder is filled in a container.
  • An inhalation solution is a liquid inhalation preparation that is inhaled using a nebulizer or the like.
  • Ivermectin or molnupiravir may be dissolved or suspended in a suitable solvent to prepare a solution or suspension.
  • An isotonizing agent, a pH adjusting agent, and the like can be added during preparation.
  • the droplet size of the inhalation solution is preferably 0.5 to 10 ⁇ m, more preferably 0.5 to 8 ⁇ m, still more preferably 0.5 to 10 ⁇ m, depending on the form of the nebulizer (jet type, ultrasonic wave type, mesh type, etc.). It may be adjusted to a droplet of 6 ⁇ m. Adjust to drops.
  • Devices that are commonly used as nebulizers can be used for the inhalation liquid of the present invention.
  • a type that uses compressed air to atomize the chemical liquid jet type
  • a type that uses the vibration of an ultrasonic transducer to atomize the chemical liquid jet type
  • a type that pushes the chemical liquid through the holes of the mesh by vibration etc. to atomize it type (mesh type) and the like.
  • An inhalation aerosol is a metered dose inhaler that can nebulize a fixed amount of ivermectin or molnupiravir together with a container filled with propellant.
  • Spray droplets to be sprayed by an inhalation aerosol are composed of ivermectin (including lyophilized products containing ivermectin and lactic acid/glycolic acid copolymer) or molnupiravir solution or suspension, filling propellant and container material.
  • ivermectin including lyophilized products containing ivermectin and lactic acid/glycolic acid copolymer
  • molnupiravir solution or suspension filling propellant and container material.
  • the droplets should preferably have a mass median diameter of 0.5 to 10 ⁇ m, more preferably 0.5 to 8 ⁇ m, still more preferably 0.5 to 6 ⁇ m.
  • ivermectin lyophilized product containing ivermectin and lactic acid/glycolic acid copolymer
  • molnupiravir is dissolved or suspended in an appropriate solvent to prepare a solution or suspension, and a liquid propellant is prepared. It can be manufactured by filling a pressure-resistant container together with it and attaching a metering valve. Dispersants, stabilizers, and the like can be added when preparing solutions or suspensions.
  • a specific example of the inhalation aerosol is a pressurized metered dose inhaler.
  • ivermectin and mornupiravir can be administered at the same time or at different times. It is also possible to use those formulated in the same dosage form. In addition, it is also possible to prepare a so-called combination drug or combination drug in which ivermectin and molnupiravir are formulated together.
  • ivermectin and mornupiravir are formulated in the same dosage form, or when a combination drug containing ivermectin and mornupiravir is formulated, it is preferable to use an oral administration formulation or an inhalant as described above. In addition, it is preferable to set the doses as described above even in the formulations and combination drugs having the same dosage form.
  • both ivermectin and mornupiravir have antiviral effects and viral growth-inhibitory effects, but their growth-inhibitory mechanisms are different from each other. Therefore, it can be expected that the antiviral action will be enhanced by the combined use of these.
  • the action of the drug of the present invention is to suppress the proliferation of viruses, it is desirable to administer it as soon as possible after SARS-CoV-2 infection is confirmed.
  • Ivermectin was pulverized with a jet mill to obtain a pulverized material.
  • the average particle size D50 of the pulverized material obtained was 2.0 ⁇ m.
  • the pulverized product and lactose hydrate were mixed with lactose hydrate so that the concentration of ivermectin was 10% to obtain an inhalable powder.
  • the formulation is shown in Table 1. Also, 0.03 g of the obtained powder was filled into a capsule to produce an inhalation powder-filled capsule.
  • Control example 1 Unpulverized ivermectin and lactose hydrate were mixed with lactose hydrate so that the concentration of ivermectin was 10% to obtain an inhalable powder.
  • the formulation is shown in Table 1. Also, 0.03 g of the obtained powder was filled into a capsule to produce an inhalation powder-filled capsule.
  • Test example 1 In order to evaluate the aerodynamic properties of the inhalable powders obtained in Example 1 and Comparative Example 1 using a device for inhalation, the fine particle content (FPF) (%) and the aerodynamic mass Dimensional diameter was measured.
  • the fine particle content (FPF) (%) and the mass median aerodynamic diameter were measured in accordance with the aerodynamic particle size measurement method for inhalants in the Japanese Pharmacopoeia 17th Edition Supplement 1, and the multi-stage Evaluated using a liquid impinger.
  • the inhalable powder of Example 1 using pulverized ivermectin had a fine particle content (FPF) (%) of 29.9% and a mass median aerodynamic diameter of 2.8 ⁇ m.
  • the inhalation powder of Comparative Example 1 using unmilled ivermectin had a fine particle content (FPF) (%) of 3.5% and a mass median aerodynamic diameter of more than 10 ⁇ m, indicating that It was considered difficult to deliver ivermectin to the deep lung.
  • the inhalation powder of Comparative Example 1 using unmilled ivermectin had a fine particle content (FPF) (%) of 3.5% and a mass median aerodynamic diameter of more than 10 ⁇ m, indicating that It was considered difficult to deliver ivermectin to
  • Example 2 Ivermectin was dissolved in ethyl alcohol, and phosphate buffer and water were added to adjust the final concentration of ivermectin to 0.5% to prepare an inhalation solution.
  • Test example 2 For the inhalation liquid obtained in Example 2, a nebulizer was used as a device to visually confirm whether the drug was sprayed in the form of mist. Further, the atomized drug was collected and the particle size was confirmed with a microscope. It was confirmed that the liquid agent of Example 2 was atomized and had a particle size of 2 to 6 ⁇ m. Therefore, it was determined that the drug solution of Example 2 is suitable as an inhalation solution.
  • Example 1 Attempts to combine treatment with tablets containing ivermectin and capsules containing mornupiravir in patients infected with SARS-CoV-2 infection and developing mild COVID-19 may reduce the risk of COVID-19.
  • Symptoms fever, cough, shortness of breath, muscle pain, nasal discharge, sore throat, headache, nausea, vomiting, abdominal pain, diarrhea, abnormal smell and abnormal taste) show improvement or disappearance.

Abstract

Provided is a novel pharmaceutical as a therapeutic medication for COVID-19.　The present invention relates to a pharmaceutical obtained by combining ivermectin and molnupiravir, a therapeutic medication for prevention and/or treatment of SARS-CoV-2 infection obtained by combining ivermectin and molnupiravir, and a therapeutic medication for prevention and/or treatment of COVID-19 obtained by combining ivermectin and molnupiravir.

Description

新規医薬New drug
　本発明は、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患の予防及び／又は治療薬に関する。 The present invention relates to preventive and/or therapeutic agents for diseases based on SARS-CoV-2 infection.
　ＣＯＶＩＤ－１９（日本名：新型コロナウイルス感染症）は、２０１９新型コロナウイルス（ＳＡＲＳ－ＣｏＶ－２）によって発症する感染症である。ＣＯＶＩＤ－１９は、２０１９年１１月に中華人民共和国の武漢で発生が確認され、同年１２月にＷＨＯに報告された感染症であり、これ以降世界的に感染が拡大している。その症状は、発熱、空咳、疲労、喀痰、息切れ、咽頭痛、頭痛、筋肉痛、関節痛、嗅覚異常、味覚異常などから始まり、重症例では肺炎が重症化して呼吸不全に陥り、死亡の転帰をとるものである。
　その感染力、罹患した際の重症化率等未だ不明な点があることに加え、新型であることから有効な治療法も未だ模索中であり、世界中の人々を不安に陥らせている。 COVID-19 (Japanese name: novel coronavirus infectious disease) is an infectious disease caused by the 2019 novel coronavirus (SARS-CoV-2). COVID-19 is an infectious disease that was confirmed to occur in Wuhan, People's Republic of China in November 2019 and was reported to WHO in December of the same year, and has spread worldwide since then. Symptoms include fever, dry cough, fatigue, sputum production, shortness of breath, sore throat, headache, muscle pain, joint pain, dysosmia, and dysgeusia. is taken.
In addition to the fact that there are still unknown points such as its infectivity and the rate of severe disease when contracted, and because it is a new type, effective treatment methods are still being sought, causing anxiety around the world.
　これまでに、多数の既存薬物のスクリーニングがなされ、イベルメクチンがＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の治療薬として期待されている（非特許文献１）。
　また、モルヌピラビル（Ｍｏｌｎｕｐｉｒａｖｉｒ）は、ウイルスのＲＮＡ複製時に複製エラーを生じさせることで抗ウイルス作用を示すことが知られており、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の治療薬として期待されている（非特許文献２） Many existing drugs have been screened so far, and ivermectin is expected as a therapeutic drug for COVID-19, a disease based on SARS-CoV-2 infection (Non-Patent Document 1).
In addition, Molnupiravir is known to exhibit antiviral effects by causing replication errors during viral RNA replication, and is expected to be a therapeutic drug for COVID-19, a disease caused by SARS-CoV-2 infection. (Non-Patent Document 2)
　本発明の課題は、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の予防及び／又は治療のための新たな医薬を提供することにある。特に、軽症や中等症のＣＯＶＩＤ－１９の予防及び／又は治療のための医薬を提供することにある。 An object of the present invention is to provide a new drug for the prevention and/or treatment of COVID-19, a disease based on SARS-CoV-2 infection. In particular, it is intended to provide a medicament for the prevention and/or treatment of mild or moderate COVID-19.
　イベルメクチンは、すでに本邦において、腸管糞線虫症および疥癬の治療薬として錠剤が用いられているが、抗ウイルス活性を有することから、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の予防及び／又は治療としても、経口投与可能な薬物として期待されている。
　また、モルヌピラビル（Ｍｏｌｎｕｐｉｒａｖｉｒ）は、抗ウイルス作用を示すことから、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の経口投与可能な治療薬として期待されている
　そこで、本発明者らは、ＳＡＲＳ－ＣｏＶ－２の感染抑制又はＣＯＶＩＤ－１９の予防及び／又は治療のために、イベルメクチン及びモルヌピラビルを組み合わせることに着目し、本発明に至った。 Ivermectin has already been used in Japan as a treatment for intestinal strongyloidiasis and scabies in tablet form. It is also expected as an orally administrable drug for treatment.
In addition, since Molnupiravir exhibits antiviral activity, it is expected as an orally administrable therapeutic agent for COVID-19, a disease based on SARS-CoV-2 infection. - The inventors have focused on combining ivermectin and mornupiravir for the suppression of CoV-2 infection or the prevention and/or treatment of COVID-19, leading to the present invention.
すなわち、本発明は、次の発明［１］～［９］を提供するものである。
［１］イベルメクチン及びモルヌピラビルを組み合わせてなる医薬。
［２］イベルメクチン及びモルヌピラビルを組み合わせてなるＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療薬。
［３］イベルメクチン及びモルヌピラビルを組み合わせてなるＣＯＶＩＤ－１９の予防及び／又は治療薬。
［４］ＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療薬製造のための、イベルメクチン及びモルヌピラビルの使用。
［５］ＣＯＶＩＤ－１９の予防及び／又は治療薬製造のための、イベルメクチン及びモルヌピラビルの使用。
［６］ＳＡＲＳ－ＣｏＶ－２感染症を予防及び／又は治療するための、イベルメクチン及びモルヌピラビルの組み合わせ。
［７］ＣＯＶＩＤ－１９を予防及び／又は治療するための、イベルメクチン及びモルヌピラビルの組み合わせ。
［８］イベルメクチン及びモルヌピラビルを投与することを特徴とする、ＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療方法。
［９］イベルメクチン及びモルヌピラビルを投与することを特徴とする、ＣＯＶＩＤ－１９の予防及び／又は治療方法。 That is, the present invention provides the following inventions [1] to [9].
[1] A pharmaceutical comprising a combination of ivermectin and mornupiravir.
[2] A prophylactic and/or therapeutic agent for SARS-CoV-2 infection, which is a combination of ivermectin and molnupiravir.
[3] A preventive and/or therapeutic agent for COVID-19, which is a combination of ivermectin and molnupiravir.
[4] Use of ivermectin and molnupiravir for prophylactic and/or therapeutic drug production for SARS-CoV-2 infection.
[5] Use of ivermectin and molnupiravir for the production of preventive and/or therapeutic agents for COVID-19.
[6] A combination of ivermectin and mornupiravir for the prevention and/or treatment of SARS-CoV-2 infection.
[7] A combination of ivermectin and mornupiravir for the prevention and/or treatment of COVID-19.
[8] A method for preventing and/or treating SARS-CoV-2 infection, which comprises administering ivermectin and molnupiravir.
[9] A method for preventing and/or treating COVID-19, which comprises administering ivermectin and molnupiravir.
　本発明のイベルメクチン及びモルヌピラビルを組み合わせてなる医薬によれば、ＳＡＲＳ－ＣｏＶ－２の感染抑制又はＣＯＶＩＤ－１９の予防及び／又は治療に効果を発揮、すなわち、ＣＯＶＩＤ－１９の症状（発熱、咳、息切れ、筋肉痛、鼻汁、咽頭痛、頭痛、嘔気、嘔吐、腹痛、下痢、臭覚異常、味覚異常）を改善又は消失する。また、イベルメクチン及びモルヌピラビルはいずれも経口投与により効果を発揮する薬物であり、従前知られるレムデシベル、カシリビマブ、イムデビマブ、ソトロビマブ等の注射剤とは異なり、投薬が簡便であることから、病院でなく、通常のクリニックでも処方や投薬が可能である。また、イベルメクチンの抗ウイルス作用の機序と、モルヌピラビルの抗ウイルス作用の機序とが異なるので、これらの併用によって抗ウイルス作用が増強されることが期待できる。 According to the medicament obtained by combining ivermectin and molnupiravir of the present invention, it is effective in suppressing SARS-CoV-2 infection or preventing and / or treating COVID-19, that is, symptoms of COVID-19 (fever, cough, Shortness of breath, muscle pain, nasal discharge, sore throat, headache, nausea, vomiting, abdominal pain, diarrhea, dysosmia, dysgeusia) are improved or eliminated. In addition, both ivermectin and molnupiravir are drugs that exert their effects when administered orally. It is possible to prescribe and administer drugs at any clinic. In addition, since the mechanism of antiviral action of ivermectin and the mechanism of antiviral action of mornupiravir are different, it is expected that the antiviral action will be enhanced by their combined use.
　本発明のイベルメクチン及びモルヌピラビルを組み合わせてなる医薬は、ＳＡＲＳ－ＣｏＶ－２の感染抑制又はＣＯＶＩＤ－１９の予防及び／又は治療に効果を発揮するものである。 The medicament obtained by combining ivermectin and molnupiravir of the present invention is effective in suppressing SARS-CoV-2 infection or preventing and/or treating COVID-19.
　本発明で用いるイベルメクチンは、イベルメクチンとして、少なくともイベルメクチンＢ1a又はイベルメクチンＢ1bのいずれかを含めばよく、イベルメクチンＢ1aとイベルメクチンＢ1bのいずれも含む混合物が好ましく、イベルメクチンＢ1aを９０％以上、イベルメクチンＢ1bを１０％未満含有する混合物がより好ましい。 The ivermectin used in the present invention may contain at least either ivermectin B1a or ivermectin B1b as ivermectin. A mixture containing both ivermectin B1a and ivermectin B1b is preferable, and 90% or more of ivermectin B1a and ivermectin Mixtures containing less than 10% B 1b are more preferred.
　本発明において、イベルメクチンは公知の化学物質であるところ、市販品を購入することやアベルメクチンを選択的触媒水素化し、次いで触媒を除去する方法等により製造することにより入手することができる。 In the present invention, ivermectin is a known chemical substance, and can be obtained by purchasing a commercial product or by producing avermectin by selective catalytic hydrogenation followed by removal of the catalyst.
　本発明のイベルメクチンを含む医薬の投与経路は特に限定されることなく、経口投与であっても、非経口投与であってもよい。
　イベルメクチンを含む医薬を経口投与する場合、その投与量は、患者の体重、年齢、性別、症状などによって異なるが、通常は成人に対して、イベルメクチンとして１日当たり０．１～１ｍｇ／ｋｇ体重とすればよく、０．１５～０．５ｍｇ／ｋｇ体重とするのが好ましく、０．２～０．４ｍｇ／ｋｇ体重とするのがより好ましいものと挙げられる。成人体重を６０ｋｇとすれば、通常、１日投与量として、６～６０ｍｇとすればよく、１２～２４ｍｇとするのが好ましい。１日投与量は、１～４回程度に分割して投与することができる。 The administration route of the ivermectin-containing medicament of the present invention is not particularly limited, and may be oral administration or parenteral administration.
When a drug containing ivermectin is administered orally, the dosage varies depending on the patient's body weight, age, sex, symptoms, etc., but the usual dose for adults is 0.1 to 1 mg/kg body weight per day as ivermectin. 0.15 to 0.5 mg/kg body weight, more preferably 0.2 to 0.4 mg/kg body weight. Assuming that the body weight of an adult is 60 kg, the daily dose is usually 6 to 60 mg, preferably 12 to 24 mg. The daily dose can be divided and administered about 1 to 4 times.
　経口投与製剤としては、カプセル剤、丸剤、顆粒剤、細粒剤、散剤、錠剤、液剤、シロップ剤、ゼリー剤、トローチ剤等を挙げることができ、これらイベルメクチンを含有する経口投与製剤は公知の方法により製造することができる。経口投与製剤の剤形としては、固形製剤が好ましく、中でもカプセル剤、丸剤、顆粒剤、細粒剤、散剤、錠剤が好ましい。
　これら経口投与製剤の投与単位当たりのイベルメクチン含有量としては、投与数量を考慮して、３ｍｇ及び６ｍｇとすることが好ましい。
　なお、日本においては、イベルメクチンを３ｍｇ含有する錠剤が発売されており、イベルメクチンがＳＡＲＳ－ＣｏＶ－２の感染抑制又はＣＯＶＩＤ－１９の予防及び／又は治療に関する承認を取得した場合、これを使用することも可能となりうる。 Examples of oral administration formulations include capsules, pills, granules, fine granules, powders, tablets, liquid formulations, syrups, jellies, lozenges, etc. Oral administration formulations containing these ivermectins are known. It can be manufactured by the method of As the dosage form of oral administration preparations, solid preparations are preferable, and capsules, pills, granules, fine granules, powders, and tablets are particularly preferable.
The ivermectin content per dosage unit of these oral administration preparations is preferably 3 mg and 6 mg in consideration of the dosage amount.
In Japan, a tablet containing 3 mg of ivermectin is on the market, and if ivermectin is approved for the suppression of SARS-CoV-2 infection or the prevention and / or treatment of COVID-19, it should be used. can also be possible.
　本発明において、モルヌピラビルは、ＩＵＰＡＣ名を（（２Ｒ，３Ｓ，４Ｒ，５Ｒ）－３，４－ｄｉｈｙｄｒｏｘｙ－５－（４－（ｈｙｄｒｏｘｙｉｍｉｎｏ）－２－ｏｘｏ－３，４－ｄｉｈｙｄｒｏｐｙｒｉｍｉｄｉｎ－１（２Ｈ）－ｙｌ）ｔｅｔｒａｈｙｄｒｏｆｕｒａｎ－２－ｙｌ）ｍｅｔｈｙｌ　ｉｓｏｂｕｔｙｒａｔｅとする、公知の化学物質であるところ、市販品を購入することや公知の方法等により製造することにより入手することができる。 In the present invention, molnupiravir has the IUPAC name ((2R,3S,4R,5R)-3,4-dihydroxy-5-(4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H) -yl) tetrahydrofuran-2-yl) methyl isobutylate, which is a known chemical substance, can be obtained by purchasing a commercially available product or by producing it by a known method.
　本発明のモルヌピラビルを含む医薬の投与経路は特に限定されることなく、経口投与であっても、非経口投与であってもよい。
　モルヌピラビルを含む医薬を経口投与する場合、その投与量は、患者の体重、年齢、性別、症状などによって異なるが、通常は成人に対して、モルヌピラビルの１日投与量として、１０～５０００ｍｇとすればよく、１００～３２００ｍｇとするのが好ましく、２００～１６００ｍｇとするのがより好ましい。１日投与量は、１～４回程度に分割して投与することができる。 The administration route of the medicament containing molnupiravir of the present invention is not particularly limited, and may be oral administration or parenteral administration.
When a drug containing molnupiravir is administered orally, the dosage varies depending on the patient's body weight, age, sex, symptoms, etc., but the usual daily dose of molnupiravir for adults is 10 to 5000 mg. Well, it is preferably 100-3200 mg, more preferably 200-1600 mg. The daily dose can be divided and administered about 1 to 4 times.
　経口投与製剤としては、カプセル剤、丸剤、顆粒剤、細粒剤、散剤、錠剤、液剤、シロップ剤、ゼリー剤、トローチ剤等を挙げることができ、これらモルヌピラビルを含有する経口投与製剤は公知の方法により製造することができる。経口投与製剤の剤形としては、固形製剤が好ましく、中でもカプセル剤、丸剤、顆粒剤、細粒剤、散剤、錠剤が好ましい。
　これら経口投与製剤の投与単位当たりのモルヌピラビル含有量としては、投与数量を考慮して、１００ｍｇ及び２００ｍｇとすることが好ましい。 Examples of oral administration formulations include capsules, pills, granules, fine granules, powders, tablets, liquid formulations, syrups, jellies, lozenges, etc. Oral administration formulations containing these molnupiravir are known. It can be manufactured by the method of As the dosage form of oral administration preparations, solid preparations are preferable, and capsules, pills, granules, fine granules, powders, and tablets are particularly preferable.
The content of molnupiravir per dosage unit of these oral administration preparations is preferably 100 mg and 200 mg in consideration of the dosage amount.
　本発明で用いるイベルメクチン及びモルヌピラビルは、それぞれ抗ウイルス作用を有することから、ＳＡＲＳ－ＣｏＶ－２が感染する部位として、下気道に直接適用できる吸入剤といった剤形は、注射剤等とは異なり、投与が簡便なことから、非経口投与の中でも、好ましい剤形として挙げることができる。
　イベルメクチン及びモルヌピラビルを下気道（気管、気管支、肺臓）にて適用するには、イベルメクチン及びモルヌピラビルの下気道への到達性の観点から、その粒子径を０．５～１０μｍとするのが好ましく、０．５～８μｍとするのがより好ましく、０．５～６μｍとするのが更に好ましい。具体的には、イベルメクチン及びモルヌピラビルの空気動力学的質量中位径をそれぞれ０．５～１０μｍとするのが好ましく、０．５～８μｍとするのがより好ましく、０．５～６μｍとするのが更に好ましい。ここで、イベルメクチン及びモルヌピラビルの粒子径は、粉末の場合はイベルメクチン含有粉末又はモルヌピラビル含有粉末の粒子径であり、液剤の場合はイベルメクチン含有噴霧液滴又は及びモルヌピラビル含有噴霧液滴の粒子径である。この粒子径は、粉末の場合は粉末製造時の粉砕、篩過などによって調整することができる。噴霧液滴の場合は、液剤を吸入する際に用いるネブライザの形態（ジェット式、超音波式、メッシュ式等）に応じて、適宜調整すればよい。 Since ivermectin and molnupiravir used in the present invention each have an antiviral effect, a dosage form such as an inhalant that can be directly applied to the lower respiratory tract as a site of SARS-CoV-2 infection can be administered unlike an injection. is convenient, it can be cited as a preferred dosage form among parenteral administration.
When applying ivermectin and mornupiravir to the lower respiratory tract (trachea, bronchi, lungs), the particle size is preferably 0.5 to 10 μm from the viewpoint of accessibility to the lower respiratory tract. 0.5 to 8 μm, more preferably 0.5 to 6 μm. Specifically, the mass median aerodynamic diameter of ivermectin and molnupiravir is preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, and more preferably 0.5 to 6 μm. is more preferred. Here, the particle size of ivermectin and molnupiravir is the particle size of the ivermectin-containing powder or molnupiravir-containing powder in the case of a powder, and the particle size of the ivermectin-containing atomized droplets or molnupiravir-containing atomized droplets in the case of a liquid formulation. In the case of powder, the particle size can be adjusted by pulverization, sieving, etc. during powder production. In the case of atomized liquid droplets, it may be appropriately adjusted according to the form of the nebulizer (jet type, ultrasonic type, mesh type, etc.) used when inhaling the liquid agent.
　吸入剤の形態としては、吸入粉末剤、吸入液剤、吸入エアゾール剤が挙げられるが、特に限定されるものではない。イベルメクチン又はモルヌピラビルの吸入剤を使用するに際しては、吸入投与のために適切な器具又は装置を使用するか、吸入用の器具を兼ね備えた容器に充填すればよい。 Forms of inhalants include inhalation powders, inhalation liquids, and inhalation aerosols, but are not particularly limited. When using an inhalant of ivermectin or molnupiravir, a suitable device or device for administration by inhalation may be used, or a container combined with a device for inhalation may be filled.
　吸入粉末剤は、吸入量が一定となるように調製したイベルメクチン含有粉末又はモルヌピラビル含有粉末のエアゾールとして吸入する製剤であり、イベルメクチン含有粉末又はモルヌピラビル含有粉末は、それぞれ、好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの粒子径を有する粉末として調製すればよく、具体的には、好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの空気動力学的質量中位径を有する粉末として調製すればよい。 The inhalable powder preparation is a preparation for inhalation as an aerosol of ivermectin-containing powder or molnupiravir-containing powder prepared so that the inhalation amount is constant. More preferably, it may be prepared as a powder having a particle size of 0.5 to 8 μm, more preferably 0.5 to 6 μm, specifically, preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm. and more preferably as a powder having a mass median aerodynamic diameter of 0.5 to 6 μm.
　イベルメクチン含有粉末又はモルヌピラビル含有粉末には、糖や糖アルコールを添加剤として用いることもできる。ここで、糖としては、乳糖水和物、白糖、ブドウ糖等を挙げることができ、糖アルコールとしては、エリスリトール、イソマルト、ラクチトール、マルチトール、マンニトール、ソルビトール、キシリトール等を挙げることができる。また、イベルメクチン含有粉末としては、特開２０１９－６９９０６号公報に記載のイベルメクチンと乳酸・グリコール酸共重合体を含む凍結乾燥物も挙げることができる。 Sugar or sugar alcohol can be used as an additive for the ivermectin-containing powder or molnupiravir-containing powder. Examples of sugars include lactose hydrate, sucrose, and glucose, and examples of sugar alcohols include erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol. Further, as the ivermectin-containing powder, a freeze-dried product containing ivermectin and a lactic acid/glycolic acid copolymer described in JP-A-2019-69906 can also be mentioned.
　吸入粉末剤の具体例としては、ドライパウダー吸入器（Ｄｒｙ　Ｐｏｗｄｅｒ　Ｉｎｈａｌｅｒ；以下、ＤＰＩと略する）を挙げることができる。本発明の吸入粉末剤に用いるデバイスはＤＰＩとして通常用いられるものを使用することができる。例えばカプセルを用いるデバイスとして、モノヘラー、ハンディヘラー、ブリーズヘラー、フローキャプス等が挙げられる。またアルミニウムのブリスターを用いるディスクヘラー、ディスカス、エリプタ等が挙げられる。
　粉末を容器に充填したリザーバ型のデバイスとして、タービュヘイラー、クリックヘラー、スイングヘラー、ツイストヘラーなどが挙げられる。 A specific example of an inhalable powder is a dry powder inhaler (hereinafter abbreviated as DPI). Devices commonly used as DPIs can be used for the inhalable powder formulation of the present invention. For example, devices using capsules include Monohaler, Handyhaler, Breezhaler, Flowcaps and the like. Other examples include Dischaler, Discus, and Ellipta, which use aluminum blisters.
Turbuhaler, Crickhaler, Swinghaler, Twisthaler and the like are examples of reservoir-type devices in which a powder is filled in a container.
　吸入液剤は、ネブライザ等により吸入する液状の吸入製剤である。イベルメクチン又はモルヌピラビルを適当な溶剤を用いて、溶解又は懸濁し、溶液又は懸濁液として調製すればよい。調製時、等張化剤やｐＨ調節剤等を添加することができる。
　吸入液剤の液滴は、ネブライザの形態（ジェット式、超音波式、メッシュ式等）に応じて、好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの液滴に調整すればよく、具体的には空気動力学的質量中位径を好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの液滴に調整すればよい。
　本発明の吸入液剤に用いるデバイスはネブライザとして通常用いられるものを使用することができる。例えば圧縮空気で薬液を霧状にするタイプ（ジェット式）、超音波振動子の振動を利用して薬液を霧状にするタイプ（ジェット式）、振動などによって薬液をメッシュの穴から押し出して霧状にするタイプ（メッシュ式）などが挙げられる。 An inhalation solution is a liquid inhalation preparation that is inhaled using a nebulizer or the like. Ivermectin or molnupiravir may be dissolved or suspended in a suitable solvent to prepare a solution or suspension. An isotonizing agent, a pH adjusting agent, and the like can be added during preparation.
The droplet size of the inhalation solution is preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, still more preferably 0.5 to 10 μm, depending on the form of the nebulizer (jet type, ultrasonic wave type, mesh type, etc.). It may be adjusted to a droplet of 6 μm. Adjust to drops.
Devices that are commonly used as nebulizers can be used for the inhalation liquid of the present invention. For example, a type that uses compressed air to atomize the chemical liquid (jet type), a type that uses the vibration of an ultrasonic transducer to atomize the chemical liquid (jet type), and a type that pushes the chemical liquid through the holes of the mesh by vibration etc. to atomize it. type (mesh type) and the like.
　吸入エアゾール剤は、容器に充填した噴射剤と共に、一定量のイベルメクチン又はモルヌピラビルを噴霧し得る定量噴霧式吸入剤である。
　吸入エアゾール剤により噴霧される噴霧液滴は、イベルメクチン（イベルメクチンと乳酸・グリコール酸共重合体を含む凍結乾燥物を含む）又はモルヌピラビルの溶液又は懸濁液の組成、充填する噴射剤や容器の部材であるノズル形状等の調整によって、好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの噴霧液滴に調整すればよく、具体的には空気動力学的質量中位径を好ましくは０．５～１０μｍ、より好ましくは０．５～８μｍ、更に好ましくは０．５～６μｍの液滴に調整すればよい。
　吸入エアゾール剤は、イベルメクチン（イベルメクチンと乳酸・グリコール酸共重合体を含む凍結乾燥物）又はモルヌピラビルを適当な溶剤を用いて、溶解又は懸濁し、溶液又は懸濁液を調製し、液状の噴射剤と共に耐圧性の容器に充填し、定量バルブを装着することにより製することができる。溶液又は懸濁液を調製するに際し、分散剤や安定化剤等を添加することができる。
　吸入エアゾール剤の具体例としては、加圧噴霧式定量吸入器（Ｍｅｔｅｒｅｄ　Ｄｏｓｅ　Ｉｎｈａｌｅｒ）を挙げることができる。 An inhalation aerosol is a metered dose inhaler that can nebulize a fixed amount of ivermectin or molnupiravir together with a container filled with propellant.
Spray droplets to be sprayed by an inhalation aerosol are composed of ivermectin (including lyophilized products containing ivermectin and lactic acid/glycolic acid copolymer) or molnupiravir solution or suspension, filling propellant and container material. By adjusting the nozzle shape, etc., it is preferable to adjust the spray droplets to preferably 0.5 to 10 μm, more preferably 0.5 to 8 μm, and still more preferably 0.5 to 6 μm. The droplets should preferably have a mass median diameter of 0.5 to 10 μm, more preferably 0.5 to 8 μm, still more preferably 0.5 to 6 μm.
For inhalation aerosols, ivermectin (lyophilized product containing ivermectin and lactic acid/glycolic acid copolymer) or molnupiravir is dissolved or suspended in an appropriate solvent to prepare a solution or suspension, and a liquid propellant is prepared. It can be manufactured by filling a pressure-resistant container together with it and attaching a metering valve. Dispersants, stabilizers, and the like can be added when preparing solutions or suspensions.
A specific example of the inhalation aerosol is a pressurized metered dose inhaler.
　本発明のイベルメクチン及びモルヌピラビルを組み合わせてなる医薬は、イベルメクチン及びモルヌピラビルを同時に又は時期をずらして投薬することができ、同時に投薬する際は、イベルメクチン及びモルヌピラビルをそれぞれ別々な剤形に製剤化したものを用いることもできるし、また、同じ剤形に製剤化したものを用いることもできる。また、イベルメクチン及びモルヌピラビルを一緒に製剤化した所謂合剤・配合剤とすることもできる。
　イベルメクチン及びモルヌピラビルを同じ剤形に製剤化する場合、またイベルメクチン及びモルヌピラビルを含む配合剤とする場合も、前記のような経口投与製剤や吸入剤などとするのが好ましい。そして、これらの同じ剤形の製剤及び配合剤においても、前述のような投与量とするのが好ましい。 In the medicament comprising a combination of ivermectin and mornupiravir of the present invention, ivermectin and mornupiravir can be administered at the same time or at different times. It is also possible to use those formulated in the same dosage form. In addition, it is also possible to prepare a so-called combination drug or combination drug in which ivermectin and molnupiravir are formulated together.
When ivermectin and mornupiravir are formulated in the same dosage form, or when a combination drug containing ivermectin and mornupiravir is formulated, it is preferable to use an oral administration formulation or an inhalant as described above. In addition, it is preferable to set the doses as described above even in the formulations and combination drugs having the same dosage form.
　本発明の医薬は、イベルメクチン及びモルヌピラビルがいずれも抗ウイルス作用、ウイルスの増殖を抑制する作用を有するものであるが、その増殖抑制作用機序は互いに相違する。従って、これらの併用によって抗ウイルス作用が増強することが期待できる。
　また、本発明の医薬は、その作用がウイルスの増殖抑制作用であるから、ＳＡＲＳ－ＣｏＶ－２感染が確認されてから早期に投与されるのが望ましい。 In the medicament of the present invention, both ivermectin and mornupiravir have antiviral effects and viral growth-inhibitory effects, but their growth-inhibitory mechanisms are different from each other. Therefore, it can be expected that the antiviral action will be enhanced by the combined use of these.
In addition, since the action of the drug of the present invention is to suppress the proliferation of viruses, it is desirable to administer it as soon as possible after SARS-CoV-2 infection is confirmed.
　以下、実施例により本発明を具体的に説明するが、本発明はこれら実施例により何ら限定されるものではない。 The present invention will be specifically described below with reference to examples, but the present invention is not limited by these examples.
参考例１
　イベルメクチンをジェットミルで粉砕し、粉砕物を得た。得られた粉砕物の平均粒子径Ｄ５０は２．０μｍであった。粉砕物と乳糖水和物をイベルメクチンの濃度が１０％となるように乳糖水和物と混合し、吸入粉末剤を得た。処方を表１に示した。また、得られた粉末０．０３ｇをカプセルに充填し、吸入粉末剤充填カプセルを製造した。 Reference example 1
Ivermectin was pulverized with a jet mill to obtain a pulverized material. The average particle size D50 of the pulverized material obtained was 2.0 μm. The pulverized product and lactose hydrate were mixed with lactose hydrate so that the concentration of ivermectin was 10% to obtain an inhalable powder. The formulation is shown in Table 1. Also, 0.03 g of the obtained powder was filled into a capsule to produce an inhalation powder-filled capsule.
対照例１
　未粉砕のイベルメクチンと乳糖水和物をイベルメクチンの濃度が１０％となるように乳糖水和物と混合し、吸入粉末剤を得た。処方を表１に示した。また、得られた粉末０．０３ｇをカプセルに充填し、吸入粉末剤充填カプセルを製造した。 Control example 1
Unpulverized ivermectin and lactose hydrate were mixed with lactose hydrate so that the concentration of ivermectin was 10% to obtain an inhalable powder. The formulation is shown in Table 1. Also, 0.03 g of the obtained powder was filled into a capsule to produce an inhalation powder-filled capsule.
試験例１
　実施例１、比較例１で得た吸入粉末剤について、吸入用器具であるデバイスを用いた空気動力学的性質の評価をするため、微粒子量（ＦＰＦ）（％）及び空気動力学的質量中位径を測定した。微粒子量（ＦＰＦ）（％）及び空気動力学的質量中位径は、日本薬局方　第十七改正第一追補の吸入剤の空気動力学的粒度測定法に準拠して、装置１のマルチステージリキッドインピンジャーを用いて評価した。
　その結果、粉砕したイベルメクチンを用いた実施例１の吸入粉末剤は、微粒子量（ＦＰＦ）（％）が２９．９％であり、また空気動力学的質量中位径は２．８μｍであったことから肺深部までイベルメクチンを到達させることが可能と考えられた。未粉砕のイベルメクチンを用いた比較例１の吸入粉末剤は、微粒子量（ＦＰＦ）（％）が３．５％であり、また空気動力学的質量中位径は１０μｍより大きかったことから肺深部までイベルメクチンを到達させることは困難と考えられた。 Test example 1
In order to evaluate the aerodynamic properties of the inhalable powders obtained in Example 1 and Comparative Example 1 using a device for inhalation, the fine particle content (FPF) (%) and the aerodynamic mass Dimensional diameter was measured. The fine particle content (FPF) (%) and the mass median aerodynamic diameter were measured in accordance with the aerodynamic particle size measurement method for inhalants in the Japanese Pharmacopoeia 17th Edition Supplement 1, and the multi-stage Evaluated using a liquid impinger.
As a result, the inhalable powder of Example 1 using pulverized ivermectin had a fine particle content (FPF) (%) of 29.9% and a mass median aerodynamic diameter of 2.8 μm. Therefore, it was considered possible to deliver ivermectin to the deep lung. The inhalation powder of Comparative Example 1 using unmilled ivermectin had a fine particle content (FPF) (%) of 3.5% and a mass median aerodynamic diameter of more than 10 μm, indicating that It was considered difficult to deliver ivermectin to
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　実施例２
　イベルメクチンをエチルアルコールで溶解し、リン酸緩衝液及び水を加え、イベルメクチンの最終的な濃度が０．５％となるように調製して吸入液剤を製造した。 Example 2
Ivermectin was dissolved in ethyl alcohol, and phosphate buffer and water were added to adjust the final concentration of ivermectin to 0.5% to prepare an inhalation solution.
試験例２
　実施例２で得られた吸入液剤について、デバイスとしてネブライザを用いて、目視にて薬剤が霧状に噴霧されるかを確認した。さらに霧状とした薬剤を採取し、顕微鏡で粒子径を確認した。実施例２の液剤は霧状に噴霧され、粒子径は２～６μｍであることが確認できた。
　したがって、実施例２の薬液は吸入液剤として適切なものであると判断した。 Test example 2
For the inhalation liquid obtained in Example 2, a nebulizer was used as a device to visually confirm whether the drug was sprayed in the form of mist. Further, the atomized drug was collected and the particle size was confirmed with a microscope. It was confirmed that the liquid agent of Example 2 was atomized and had a particle size of 2 to 6 μm.
Therefore, it was determined that the drug solution of Example 2 is suitable as an inhalation solution.
実施例１
　ＳＡＲＳ－ＣｏＶ－２感染に感染し、軽症ＣＯＶＩＤ－１９を発症した患者にイベルメクチンを含有する錠剤を投与し、またモルヌピラビルを含有するカプセル剤を投与するといった組み合わせた治療を試みると、ＣＯＶＩＤ－１９の症状（発熱、咳、息切れ、筋肉痛、鼻汁、咽頭痛、頭痛、嘔気、嘔吐、腹痛、下痢、臭覚異常や味覚異常）が改善ないし消失効果を示す。 Example 1
Attempts to combine treatment with tablets containing ivermectin and capsules containing mornupiravir in patients infected with SARS-CoV-2 infection and developing mild COVID-19 may reduce the risk of COVID-19. Symptoms (fever, cough, shortness of breath, muscle pain, nasal discharge, sore throat, headache, nausea, vomiting, abdominal pain, diarrhea, abnormal smell and abnormal taste) show improvement or disappearance.

Claims (9)

  1. 　イベルメクチン及びモルヌピラビルを組み合わせてなる医薬。 A drug that combines ivermectin and molnupiravir.
  2. 　イベルメクチン及びモルヌピラビルを組み合わせてなるＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療薬。 A prophylactic and/or therapeutic agent for SARS-CoV-2 infection, which is a combination of ivermectin and molnupiravir.
  3. 　イベルメクチン及びモルヌピラビルを組み合わせてなるＣＯＶＩＤ－１９の予防及び／又は治療薬。 A drug for the prevention and/or treatment of COVID-19 that combines ivermectin and molnupiravir.
  4. 　ＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療薬製造のための、イベルメクチン及びモルヌピラビルの使用。 　The use of ivermectin and molnupiravir for the prophylactic and/or therapeutic manufacture of SARS-CoV-2 infections.
  5. 　ＣＯＶＩＤ－１９の予防及び／又は治療薬製造のための、イベルメクチン及びモルヌピラビルの使用。 　The use of ivermectin and molnupiravir for the production of prophylactic and/or therapeutic agents for COVID-19.
  6. 　ＳＡＲＳ－ＣｏＶ－２感染症を予防及び／又は治療するための、イベルメクチン及びモルヌピラビルの組み合わせ。 A combination of ivermectin and molnupiravir for the prevention and/or treatment of SARS-CoV-2 infection.
  7. 　ＣＯＶＩＤ－１９を予防及び／又は治療するための、イベルメクチン及びモルヌピラビルの組み合わせ。 A combination of ivermectin and mornupiravir for the prevention and/or treatment of COVID-19.
  8. 　イベルメクチン及びモルヌピラビルを投与することを特徴とする、ＳＡＲＳ－ＣｏＶ－２感染症の予防及び／又は治療方法。 A method for preventing and/or treating SARS-CoV-2 infection, which comprises administering ivermectin and molnupiravir.
  9. 　イベルメクチン及びモルヌピラビルを投与することを特徴とする、ＣＯＶＩＤ－１９の予防及び／又は治療方法。 A method for preventing and/or treating COVID-19, characterized by administering ivermectin and molnupiravir.
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