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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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • 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
  • 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
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • 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 an inhalant containing cepharanthin.
• COVID-19 Japanese name: new coronavirus infection
• SARS-CoV-2 2019 new 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 the infection has spread worldwide since then.
• the symptoms begin with fever, dry cough, fatigue, sputum, shortness of breath, sore throat, headache, myalgia, arthralgia, olfactory dysfunction, taste dysfunction, etc.
• pneumonia becomes severe and causes respiratory failure, resulting in death. Is to take.
• Non-Patent Document 1 a large number of existing drugs have been screened, and recently, cepharanthin is expected as a therapeutic agent for COVID-19.
• An object of the present invention is to provide a new drug for the prevention and / or treatment of a disease based on SARS-CoV-2 infection, COVID-19.
• cepharanthin powders and tablets for oral administration, and injections are used.
• the present inventors have conceived to apply cepharanthin, which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most infected with SARS-CoV-2.
• cepharanthin as an inhaler that can be directly applied to the lower respiratory tract, and further, by setting the particle size of cepharanthin to 0.5 to 10 ⁇ m, the efficiency of cepharanthin directly to the lower respiratory tract is achieved.
• the present invention has been completed by finding that a well-supplyable inhaler can be obtained.
• the present invention provides an inhalant containing cepharanthin. Further, when the particle diameter of cepharanthin is 0.5 to 10 ⁇ m as the aerodynamic particle diameter and the median diameter of the aerodynamic mass of cepharanthin is 0.5 to 10 ⁇ m, cepharanthin efficiently reaches the lower respiratory tract.
• cepharanthin which is considered to be an effective drug for suppressing infection of SARS-CoV-2, can be directly supplied to the lower respiratory tract.
• the inhalant of the present invention is a preparation that inhales cepharanthin as an aerosol and applies it to the lower respiratory tract.
• Cepharanthine used in the present invention is a chemical substance having a chemical name of 6', 12'-Dimethoxy-2, 2'-dimethyl-6,7- [methylenebis (oxy)] oxyacanthan, and is a chemical substance having a chemical name of 6', 12'-Dimethoxy-2, 2'-Dimethyl-6,7- , A type of alkaloid that can be extracted from Stephania japonica, etc.
• Cepharanthine is used to treat leukopenia caused by radiation, alopecia areata / alopecia areata, serous glue ear, and pit viper bite.
• cepharanthin is used as an inhaler as in the present invention, in addition to these indications, it is particularly useful as an infection suppressant for SARS-CoV-2 and a prophylactic and / or therapeutic agent for COVID-19.
• cepharanthin either chemically synthesized cepharanthin or extracted from Tuzla japonica, Menispermaceae japonica, Stephania japonica, etc. can be used.
• Tamasaki Tsuzurafuji it is also possible to use Tamasaki Tsuzurafuji extract containing other alkaloids other than cepharanthin such as isotetrandrine, cycleanin, and velbamine in addition to cepharanthin.
• Cepharanthine and Tamasaki Tsuzurafuji extract are commercially available and can be purchased and used, and Tamasaki Tsuzurafuji extract can be produced from Tamasaki Tsuzurafuji by using a known method.
• the particle size of cepharanthin is 0.5 to 10 ⁇ m from the viewpoint of reachability to the lower respiratory tract. It is more preferably 8 ⁇ m, and even more preferably 2 to 8 ⁇ m.
• the aerodynamic mass median diameter of cepharanthin is preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, and even more preferably 2 to 8 ⁇ m.
• the particle size of cepharanthin is the particle size of the cepharanthin-containing powder in the case of powder, and the particle size of the spray droplet containing cepharanthin in the case of a liquid agent.
• this particle size can be adjusted by pulverization, sieving, etc. at the time of powder production.
• spray 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.
• the form of the inhalant of the present invention includes, but is not limited to, an inhalation powder agent, an inhalation liquid agent, and an inhalation aerosol agent.
• an appropriate device or device for inhalation administration may be used, or a container including an inhalation device may be filled.
• the inhalation powder is a preparation to be inhaled as an aerosol of a cepharantin-containing powder prepared so that the inhalation amount is constant, and the cepharantin-containing powder is preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, still more preferably. It may be prepared as a powder having a particle size of 2 to 8 ⁇ m, specifically, an aerosol medium diameter of preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, still more preferably 2 to 8 ⁇ m. It may be prepared as a powder having. Sugar or sugar alcohol can also be used as an additive in the cepharanthin-containing powder.
• examples of sugar include lactose hydrate, sucrose, glucose and the like
• examples of sugar alcohols include erythritol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol and the like.
• Specific examples of the inhalation powder agent include a dry powder inhaler (hereinafter abbreviated as DPI).
• DPI dry powder inhaler
• the device usually used as DPI can be used.
• a device using a capsule includes a monohaler, a handy heller, a breeze heller, a flow cap, and the like.
• Reservoir-type devices filled with powder in a container include a turbuler, a click heller, a swing heller, a twist heller, and the like.
• the inhalation solution is a liquid inhalation preparation that is inhaled by a nebulizer or the like.
• Cepharanthine may be dissolved or suspended in a suitable solvent to prepare a solution or suspension.
• an tonicity agent, a pH adjuster, or the like can be added.
• the droplet of the inhalant liquid is preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, still more preferably 2 to 8 ⁇ m, depending on the form of the nebulizer (jet type, ultrasonic type, mesh type, etc.).
• the aerodynamic mass median diameter may be adjusted to a droplet of preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, still more preferably 2 to 8 ⁇ m.
• cepharanthin registered trademark
• cepharanthin (registered trademark) Note manufactured and sold by Medisa Shinyaku Co., Ltd. can be used.
• cepharanthin (registered trademark) injection may be used as it is or diluted with an appropriate solvent and inhaled using a nebulizer.
• a device used for the inhalation solution of the present invention a device usually used as a nebulizer can be used.
• a type that atomizes the chemical solution with compressed air (jet type)
• a type that atomizes the chemical solution using the vibration of an ultrasonic vibrator (jet type)
• a mist that pushes the chemical solution out of a hole in the mesh by vibration
• An example is a type (mesh type) that makes a shape.
• the inhalation aerosol is a fixed-quantity spray inhaler that can spray a certain amount of cepharanthin together with the propellant filled in the container.
• the spray droplet sprayed by the inhalation aerosol agent is preferably 0.5 to 10 ⁇ m, more preferably 0.5 to 10 ⁇ m, depending on the composition of the solution or suspension of cepharanthin, the propellant to be filled, the shape of the nozzle which is a member of the container, and the like.
• the spray droplets may be adjusted to 1 to 8 ⁇ m, more preferably 2 to 8 ⁇ m, and specifically, the aerodynamic mass medium diameter is preferably 0.5 to 10 ⁇ m, more preferably 1 to 8 ⁇ m, still more preferably.
• Inhalation aerosols are made by dissolving or suspending cepharanthin in a suitable solvent, preparing a solution or suspension, filling a pressure resistant container with a liquid propellant, and installing a metering valve. be able to. Dispersants, stabilizers and the like can be added when preparing the solution or suspension. Specific examples of the inhalation aerosol agent include a pressurized dose inhaler.
• the inhalant of the present invention is an alopecia areata / alopecia areata, serous glue ear, and pit viper bite, which are indications for cepharanthin, as well as a SARS-CoV-2 infection inhibitor, COVID-19 prevention and /.
• it can be used as a therapeutic agent.
• the dose varies depending on the weight, age, sex, symptoms, etc. of the patient, but usually, for adults, the range of cepharanthin is in the range of 1 to 20 mg per day.
• the inhalant of the present invention when used as an infection inhibitor of SARS-CoV-2, a prophylactic and / or therapeutic agent of COVID-19, it can be used in combination with an anti-HIV agent such as nelfinavir.
• Example 1 98.5 g of lactose hydrate was added to 1.5 g of cepharanthin crushed by a jet mill (particle size: 1.2 ⁇ m: measured by laser diffraction method), and Hiflex Gural (manufactured by Fukae Pautech Co., Ltd., HF-GS-). 2J) was mixed. 0.1 g of the obtained powder was filled in a capsule to produce an inhalation powder.
• Comparative Example 1 Add 98.5 g of lactose hydrate to 1.5 g of unground cepharanthin (particle size: 50 ⁇ m: measured by laser diffraction method) and mix with Hiflex Gural (manufactured by Fukae Pautech Co., Ltd., HF-GS-2J). bottom. 0.1 g of the obtained powder was filled in a capsule to produce an inhalation powder.
• Test Example 1 For the inhalation powders obtained in Example 1 and Comparative Example 1, the Stage 2 display rate (%) and the amount of fine particles (FPD) (%) were measured using a monoherer as a device. The results are shown in Table 1.
• Amount of fine particles (FPD) (%) was made using the multi-stage liquid impinger of the device 1 in accordance with the aerodynamic particle size measurement method of the inhalant of the 17th revision of the Japanese Pharmacopoeia.
• the inhaled powder of Example 1 has a high Stage 2 display rate (%) and fine particle amount (FPD) (%) of about 30%, and can reach deep lungs with cepharanthin. It was considered possible.
• the Stage 2 display rate (%) and the amount of fine particles (FPD) (%) were as low as about 3%, and it was considered difficult to reach the deep lung.
• Example 2 1.5 g of cepharanthin was suspended in 100 g of sterile purified water with a stirrer, 0.1 g of trometamol and 0.1 g of ethanol were added and dissolved, and 0.7 g of sodium chloride was added and dissolved to produce an inhalant.
• Cepharanthine (registered trademark) was injected to make an inhalation solution.
• Cepharanthine® Note 10 mg contains an appropriate amount of cepharanthin 10 mg as an active ingredient, benzyl alcohol 40 mg, sodium chloride 20 mg, and hydrochloric acid as additives in 2 mL (see the package insert of Cepharanthine® Note 10 mg). ).
• Test Example 2 With respect to the inhalation liquids obtained in Examples 2 and 3, it was visually confirmed whether the medicine was sprayed in the form of a mist using a nebulizer as a device. Furthermore, the atomized drug was collected and the particle size was confirmed with a microscope. The results are shown in Table 2. When the liquid was sprayed in the form of mist, a circle was marked in the table.
• Example 2 the chemical solution is sprayed in the form of a mist, and the particle size thereof is about 4 ⁇ m in Example 2 and about 5 ⁇ m in Example 3, and the chemical solutions of Examples 2 and 3 are suitable as an inhalation solution. I decided that.

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• 2021
  • 2021-05-14 PH PH1/2022/553084A patent/PH12022553084A1/en unknown
  • 2021-05-14 JP JP2022522211A patent/JPWO2021230340A1/ja active Pending
  • 2021-05-14 AU AU2021270426A patent/AU2021270426A1/en not_active Abandoned
  • 2021-05-14 US US17/998,308 patent/US20230338365A1/en not_active Abandoned
  • 2021-05-14 WO PCT/JP2021/018328 patent/WO2021230340A1/ja not_active Ceased
  • 2021-05-14 EP EP21804702.5A patent/EP4151211A1/en not_active Withdrawn
  • 2021-05-14 KR KR1020227038651A patent/KR20230011282A/ko not_active Withdrawn
  • 2021-05-14 CN CN202180035149.1A patent/CN117083063A/zh active Pending

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