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WO2023080189A1 - Medicinal product - Google Patents

Medicinal product Download PDF

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Publication number
WO2023080189A1
WO2023080189A1 PCT/JP2022/041114 JP2022041114W WO2023080189A1 WO 2023080189 A1 WO2023080189 A1 WO 2023080189A1 JP 2022041114 W JP2022041114 W JP 2022041114W WO 2023080189 A1 WO2023080189 A1 WO 2023080189A1
Authority
WO
WIPO (PCT)
Prior art keywords
cepharanthine
capsule
particle size
packaging
capsules
Prior art date
Application number
PCT/JP2022/041114
Other languages
French (fr)
Japanese (ja)
Inventor
英輝 小澤
隆宏 森
Original Assignee
興和株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 興和株式会社 filed Critical 興和株式会社
Publication of WO2023080189A1 publication Critical patent/WO2023080189A1/en

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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
    • A61K31/435—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
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K47/26—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
    • 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 pharmaceuticals containing cepharanthine.
  • 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.
  • Many existing drugs have been screened so far, and recently, cepharanthine is expected as a therapeutic drug for COVID-19 (Non-Patent Document 1).
  • 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.
  • cepharanthine is currently used as an oral dosage form of powder and tablets, as well as an injection.
  • the present inventors came up with the idea of applying cepharanthine, which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most infected with SARS-CoV-2.
  • cepharanthine which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most infected with SARS-CoV-2.
  • the object can be achieved by making cepharanthine into an inhaler that can be directly applied to the lower respiratory tract. It has been found that a well deliverable inhalant is obtained.
  • cepharanthine with a particle size of 0.5 to 10 ⁇ m and lactose with a particle size of 1 to 200 ⁇ m are enclosed in a capsule, and the capsule is further enclosed in an airtight package containing an inert gas and / or an oxygen scavenger.
  • the present inventors have found that a drug containing cepharanthine-containing capsules with excellent storage stability can be obtained by housing the container, and completed the present invention.
  • the present invention provides the following inventions [1] to [6].
  • a pharmaceutical product containing capsules containing (a) cepharanthine with an average particle size of 0.5 to 10 ⁇ m and (b) lactose with an average particle size of 1 to 200 ⁇ m in an airtight package, wherein the airtight package A drug in which an inert gas and/or an oxygen scavenger is enclosed in the body.
  • [4] The drug according to any one of [1] to [3], wherein the content of component (a) in one capsule is 0.01 to 40 mg.
  • [5] The drug according to any one of [1] to [4], wherein component (b) in the capsule is lactose hydrate.
  • [6] The drug according to any one of [1] to [5], wherein the inert gas is a gas selected from nitrogen, helium, argon, neon, krypton, radon, xenon and carbon dioxide.
  • the medicinal product of the present invention comprises capsules containing fine powder of cepharanthine and lactose and contained in an airtight package containing an inert gas or an oxygen scavenger. , can efficiently supply cepharanthine to the lower respiratory tract.
  • the capsule contained in the airtight package of the pharmaceutical of the present invention contains (a) cepharanthine with a particle size of 0.5-10 ⁇ m and (b) lactose with a particle size of 1-200 ⁇ m.
  • Cepharanthine the component (a) used in the present invention, is a chemical substance with the chemical name of 6′,12′-Dimethoxy-2,2′-dimethyl-6,7-[methylenebis(oxy)]oxycanthan. It is a kind of alkaloids that can be extracted from tsuzurafuji, koutou tsuzurafuji, lotus vine, and the like. Cepharanthine is used to treat radiation-induced leukopenia, alopecia areata/alopecia pityriasis, otitis media with effusion, and viper bites. When cepharanthine is used as an inhalant as in the present invention, in addition to these indications, it is particularly useful as a SARS-CoV-2 infection inhibitor and a COVID-19 preventive and/or therapeutic agent.
  • cepharanthine can be used either chemically synthesized or extracted from Tamasakitsutsurafuji, Koutoutsutsurafuji, Lotus japonicum, and the like.
  • an extract containing other alkaloids other than cepharanthine such as isotetrandrine, cyclanine, and berbamine, in addition to cepharanthine.
  • Cepharanthine and extracts of Rhubarb japonicum are commercially available and can be purchased and used, and the extract of Rhubarb japonicum can be produced from R. raffi by using a known method.
  • the particle size is preferably from 0.5 to 10 ⁇ m, and from 1 to 10 ⁇ m. 8 ⁇ m is more preferable, and 2 to 8 ⁇ m is even more preferable.
  • the particle diameter means the cumulative frequency 50% diameter obtained by a laser diffraction/scattering particle size distribution measurement method (Partica LA-950V2: Horiba, Ltd.) (hereinafter sometimes referred to as D50).
  • the particle size can be adjusted by pulverization, sieving, or the like during production.
  • the content of cepharanthine in one capsule is preferably a single dose, preferably 0.01 to 40 mg, more preferably 0.1 to 30 mg, and preferably 1 to 20 mg. More preferred.
  • Capsules can be divided into about 1 to 3 times a day, and 1 to 8 capsules (preferably 1 to 4 capsules, particularly preferably 1 to 2 capsules) can be taken before meals, between meals, after meals, before bedtime, etc. .
  • Lactose of component (b) used in the present invention is an excipient.
  • lactose it is preferable to use lactose hydrate.
  • the particle size of lactose is preferably 1 to 200 ⁇ m, more preferably 1 to 180 ⁇ m, in consideration of accessibility to the lower respiratory tract and storage stability of cepharanthine. The particle size can be adjusted by pulverization, sieving, or the like during production.
  • lactose is used by mixing (b1) fine lactose with a particle size of 1 to 50 ⁇ m and (b2) lactose with a particle size of 50 to 200 ⁇ m, from the viewpoint of cepharanthin accessibility to the lower respiratory tract and storage stability. is more preferable.
  • the particle size of fine lactose is preferably 1 to 40 ⁇ m, more preferably 1 to 30 ⁇ m, even more preferably 1 to 20 ⁇ m.
  • the particle size of lactose having a particle size of 50 to 200 ⁇ m is preferably 70 to 180 ⁇ m, more preferably 80 to 160 ⁇ m, even more preferably 100 to 150 ⁇ m.
  • the content mass ratio (b1/b2) of fine lactose and lactose with a particle size of 50 to 200 ⁇ m is preferably 0.0001 to 0.5, more preferably 0.001 to 0.2, and 0.01 to 0. .1 is more preferred.
  • the content mass ratio (a/b) of component (a) and component (b) is 0.001 to 0.5 from the viewpoint of accessibility of cepharanthine to the lower respiratory tract, storage stability and ease of powder inhalation. is preferred, 0.005 to 0.25 is more preferred, and 0.01 to 0.1 is even more preferred.
  • Capsules used in the present invention contain acetic acid, phosphoric acid, boric acid, citric acid, tartaric acid, lactic acid, aspartic acid, histidine, arginine, lysine, glycine, glutamic acid, in addition to the above components (a) and (b).
  • ⁇ -aminocaproic acid sulfuric acid and their pharmaceutically acceptable salts
  • pH adjusters such as sodium hydroxide and hydrochloric acid, parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate, benzalkonium chloride, or Preservatives such as chlorobutanol, stabilizers such as sodium cromoglycate, preservatives such as kaatresin, phenol, sodium bisulfite, sodium edetate, sodium chloride, carmellose sodium, xylitol, glycerin, creatinine, magnesium stearate, nicotinic acid Stabilizers such as amide, macrogol (600, 4000, etc.), tocopherol and its derivatives, sodium nitrite, sodium sulfite, ascorbic acid, etc., bases such as oleic acid, purified oleic acid, purified water, absolute ethanol, etc.
  • Solubilizers, solvents such as water for injection, etc. can be contained, but the content thereof is preferably 5% by mass or less, more preferably 3% by mass or less, relative to the total amount of capsule contents. It is preferably 2% by mass or less, and more preferably 2% by mass or less.
  • the capsule of the present invention is preferably a hard capsule, and the shell thereof includes gelatin, hydroxypropylmethylcellulose, polyvinyl alcohol copolymer, pullulan and the like, and hydroxypropylmethylcellulose is particularly preferable from the viewpoint of stability.
  • Commercially available products include, for example, Japanese Pharmacopoeia gelatin capsules containing PEG (macrogol) (Qualicaps Co., Ltd.), Qualy V TM (Qualicaps Co., Ltd.) and Vcaps TM Plus (Lonza Japan Co., Ltd.) based on hydroxypropyl methylcellulose. company), polyvinyl alcohol copolymer-based PONDAC TM capsules (Nissin Kasei Co., Ltd.), and pullulan-based NPcaps TM (Lonza Japan Co., Ltd.).
  • the capsule of the present invention can be used as an orally administered drug, it is preferably used as an inhalation powder capsule from the viewpoint of allowing cepharanthine to reach the lower respiratory tract.
  • a device or device suitable for inhalation administration may be used.
  • DPI dry powder inhaler
  • Devices commonly used as DPIs can be used for the inhalable powder capsules of the present invention.
  • devices include Monohaler, Handyhaler, Breezhaler, Flowcaps, and the like.
  • the capsules are further housed in an airtight package containing an inert gas and/or an oxygen scavenger and supplied as a pharmaceutical product.
  • the "airtight package” means a package that can substantially prevent solid and liquid from entering from the outside of the package under normal handling, transportation, storage, etc. This concept includes “airtight container” and “sealed container” defined in the General Rules.
  • the packaging body both fixed and irregular shapes can be used, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, and the like. is mentioned. In the present invention, more than one of these may be combined, and a specific example thereof is a form in which the capsules are first packaged by PTP packaging and then further packaged by pillow packaging.
  • the packaging material (material) for the airtight package is not particularly limited as long as it can normally exhibit moisture resistance, and materials used for the purpose of moisture-proofing contents that are vulnerable to moisture in the fields of pharmaceuticals and foods are used. It can be used as appropriate.
  • the material of the bottle body used for bottle packaging include glass, plastic (polyester, polyethylene (including low density (LDPE) and high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum), and the like. mentioned.
  • Materials for the stopper and lid include, for example, plastics (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), and the like.
  • a suitable number of capsules may be stored in a commercially available bottle and then sealed with a suitable stopper or lid.
  • the size of the bottle may be appropriately selected according to the number of capsules to be stored. more preferred.
  • polyethylene and polypropylene are preferable, low density polyethylene (LDPE) and high density polyethylene (HDPE) are more preferable, and high density polyethylene (HDPE) is particularly preferable.
  • Examples of packaging materials used for SP packaging, PTP packaging, pillow packaging and stick packaging include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose-modified PET (PET-G), biaxial Oriented nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP) , ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC ), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid vinyl chloride (VSC) and other resins, and metal
  • a multi-layer structure in which two or more of these are appropriately combined.
  • Examples of such a multilayer structure include a laminate of PVC and PVDC (PVC/PVDC, hereinafter abbreviated in the same way), PVC/PVDC/PE/PVC, PVC/PVDC/PE/PVDC/PVC, CPP/COC/CPP, PVC/AL, CPP/AL, CPP/CPP/CPP and the like.
  • Methods for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination and heat lamination.
  • Polyvinyl chloride and aluminum foil are preferable as packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like.
  • a desired number of the capsules are stored in pockets formed on a resin sheet or the like by a known method, and then a sheet made of metal foil such as aluminum foil is used as a constituent material.
  • a sheet made of metal foil such as aluminum foil
  • it can be used as a lid material to form a lid.
  • a so-called double-sided aluminum PTP package using a sheet made of aluminum foil as a constituent material of the pocket forming sheet may also be used.
  • a sheet or the like having PTP aluminum foil as a constituent material is used to package capsules one by one or by one dosage unit.
  • the occupancy rate (volume ratio) of the capsule inside the package is usually 25 to 90%, preferably 28 to 80%, and 30 to 90% when the package is bottle packaging. 70% is more preferred.
  • the package is SP packaging, PTP packaging, pillow packaging or stick packaging, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%.
  • the occupancy ratio means the occupancy ratio of the capsule to the internal volume of the package. It is not taken into account when calculating space occupancy.
  • a commercially available package may be used as it is as an airtight package, or a commercially available packaging material may be processed and used.
  • Examples of such commercially available products include the Z-series (manufactured by Hanshin Kasei Kogyo Co., Ltd.), etc., as packaging bodies for bottle packaging.
  • Packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include SUMILITE VSS, SUMILITE VSL, SUMILITE NS, SUMILITE FCL (manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Taisei Kako Co., Ltd.), and PTP.
  • Vinyl Foil for PTP Super Foil for PTP (manufactured by Mitsubishi Plastics Co., Ltd.), Nippaku Aluminum Foil (manufactured by Nippon Foil Co., Ltd.), Aluminum Foil Silver Plain (manufactured by Daiwa Chemical Industry Co., Ltd.), and the like.
  • an inert gas and/or an oxygen scavenger are enclosed in the airtight package housing the capsule.
  • the storage stability of the cepharanthine powder in the capsule is improved by enclosing an inert gas and/or an oxygen scavenger. Specifically, the production of cepharanthine-related substances is suppressed.
  • Inert gases include nitrogen, helium, argon, neon, krypton, radon, xenon, and carbon dioxide.
  • nitrogen gas, argon gas, and the like are more preferable from the viewpoint of availability, safety, and the like. Encapsulation of inert gas can be achieved by replacing the air in the airtight package with inert gas to reduce oxygen as much as possible.
  • oxygen scavengers include metal powders such as iron powder, inorganic substances such as ferrous salts, dithionites, sulfites, and metal halides, ascorbic acid, erythorbic acid, salts thereof, and hydroquinone.
  • Various substances are known, such as those mainly composed of organic compounds such as polyphenols such as catechol and catechol.
  • self-reacting type and moisture-dependent type oxygen scavengers and both of them can be used in the present invention.
  • Commercially available products include "Ageless” (trade name) S type, SS type, Z type, FX type, ZM type, SA type, GL type, and “Pharma Keep” (trade name) manufactured by Mitsubishi Gas Chemical Co., Ltd.
  • the oxygen absorber preferably has an oxygen absorption amount (oxygen absorption amount per oxygen absorber: mL) of 10 mL or more, more preferably 20 mL or more, and even more preferably 25 mL or more. Also, the oxygen absorber is preferably used as an oxygen absorber for foods with a high water activity value (AW), and the range of application to foods (water activity value) is 0.3 or more. preferable.
  • AW water activity value
  • the capsule is first packaged in PTP packaging and then further packaged in pillow packaging. Encapsulation of the agent is preferred.
  • the pharmaceutical of the present invention is a SARS-CoV-2 infection inhibitor, prevention of COVID-19 and / or It can be used as a therapeutic agent.
  • the dose varies depending on the patient's body weight, age, sex, symptoms, etc., but is usually in the range of 1 to 20 mg of cepharanthine per day for adults.
  • the drug of the present invention when used as a SARS-CoV-2 infection inhibitor or a COVID-19 prophylactic and/or therapeutic drug, it can be used in combination with an anti-HIV agent such as nelfinavir.
  • Reference example 1 98.5 g of lactose hydrate was added to 1.5 g of cepharanthine pulverized by a jet mill (particle size: 1.2 ⁇ m: measured by laser diffraction method), and Hiflex Gral (Fukae Powtech Co., Ltd., HF-GS- 2J). 0.1 g of the resulting powder was filled into capsules to produce an inhalable powder.
  • Reference Comparative Example 1 98.5 g of lactose hydrate was added to 1.5 g of unground cepharanthine (particle size: 50 ⁇ m: measured by laser diffraction method) and mixed with Hiflex Gral (manufactured by Fukae Powtec Co., Ltd., HF-GS-2J). bottom. 0.1 g of the resulting powder was filled into capsules to produce an inhalable powder.
  • Test example 1 For the inhalable powders obtained in Reference Example 1 and Reference Comparative Example 1, the Stage 2 display rate (%) and the fine particle content (FPD) (%) were measured using a monohaler as a device. Table 1 shows the results. (1) Stage2 display rate (%) Using a Twin Impinger, which is an in vitro evaluation device for inhalants, the Stage 2 display rate, which is the airway reach rate, was determined. (2) Fine particle amount (FPD) (%) Evaluation was performed using a multi-stage liquid impinger of Apparatus 1 in accordance with the aerodynamic particle size measurement method for inhalants of the Japanese Pharmacopoeia 17th Edition, Second Supplement.
  • the inhalation powder of Reference Example 1 has a Stage 2 display rate (%) and a fine particle content (FPD) (%) as high as about 30%, and cepharanthine can reach the deep lung. considered possible.
  • the Stage 2 display rate (%) and the fine particle content (FPD) (%) were as low as about 3%, and it was considered difficult for cepharanthine to reach the deep lung. .
  • sample 1 2 g of cepharanthine (D50: 133 ⁇ m) was placed in a glass bottle (2K standard bottle) to obtain sample 1.
  • sample 2 2 g of cepharanthine (D50: 3.5 ⁇ m) pulverized by a jet mill was placed in a glass bottle (2K standard bottle) to obtain sample 2.
  • sample 3 2 g of cepharanthine (D50: 3.5 ⁇ m) pulverized by a jet mill and 18 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120) were mixed and placed in a glass bottle (2K standard bottle) to obtain sample 3.
  • Example 4 2 g of cepharanthine (D50: 3.5 ⁇ m) pulverized with a jet mill and 18 g of lactose hydrate (D50: 8.1 ⁇ m, trade name: InhaLac TM 400) were mixed, placed in a glass bottle (2K standard bottle), and sample 4 and bottom.
  • cepharanthine D50: 3.5 ⁇ m
  • lactose hydrate D50: 8.1 ⁇ m, trade name: InhaLac TM 400
  • Test example 2 For each of the above samples, the ratio of cepharanthine-derived decomposition products (related substances) before the start of storage and after storage for 3 days at 80° C. was measured using an HPLC device. Specifically, the proportion of cepharanthine-related substances was measured as an area percentage (%) with respect to the total peak area derived from cepharanthine and its related substances. Then, from the ratio (%) of cepharanthine related substances before the start of storage and after storage for 3 days at 80 ° C. for various samples obtained, according to the following formula, the increase rate (%) of degradation products derived from cepharanthine for each sample ) was calculated.
  • Decomposition products were quantified by liquid chromatography under the following conditions. Detector: UV absorption photometer (measurement wavelength: 284 nm) Column temperature: Constant temperature around 40° C. Column: Octadecylsilylated silica gel for liquid chromatography (4.6 mm ⁇ 15 cm, ⁇ 5 ⁇ m) Mobile phase: acetonitrile/diluted triethylamine (1 ⁇ 2000) mixture (1:1)
  • Table 2 shows the results obtained. From Table 2, it was found that the storage stability of cepharanthine decreased when it was finely powdered. Cepharanthine showed reduced storage stability even when mixed with lactose.
  • Production example 1 2 g of cepharanthine (D50: 3.5 ⁇ m) pulverized by a jet mill, 17.26 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG), and lactose hydrate 0.74 g (D50: 8.1 ⁇ m, trade name: InhaLac TM 400, sales company: MEGGLE GmbH & CO. KG) was mixed to obtain a powder.
  • cepharanthine D50: 3.5 ⁇ m
  • lactose hydrate D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG
  • lactose hydrate 0.74 g D50: 8.1 ⁇ m, trade name: InhaLac TM 400, sales company: MEGGLE GmbH & CO. KG
  • Example 1 The powder obtained in Production Example 1 was filled in No. 3 HPMC capsules (trade name: Vcaps TM Plus (white), sales company: Lonza Japan Co., Ltd.) so that each capsule contained 100 mg, and 200 capsules were prepared. Five capsules thus obtained were placed in a glass bottle (2K standard bottle) to prepare a pharmaceutical preparation.
  • HPMC capsules trade name: Vcaps TM Plus (white), sales company: Lonza Japan Co., Ltd.
  • Comparative example 1 100 mg of the powder obtained in Production Example 1 was placed in a glass bottle (2K standard bottle) to prepare a pharmaceutical preparation.
  • Test example 3 For each of the above samples, the ratio of cepharanthine-derived related substances before the start of storage and after storage at 60° C. for 2 weeks was measured using an HPLC device.
  • Example 2 The 5 capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle), and the air in the glass bottle was replaced with nitrogen to prepare a drug.
  • Example 3 Five capsules obtained in Example 1 and one deoxidant (12.7 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS SS-300) were placed in a glass bottle (7K standard bottle) to prepare a drug.
  • Comparative example 2 Five capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle) to prepare a drug.
  • Test example 4 For each of the samples of Examples 2 and 3 and Comparative Example 2, the ratio of cepharanthine-derived decomposition products (related substances) before the start of storage and after storage at 60° C. for 4 weeks was measured using an HPLC device. As a result, as shown in Table 4, by enclosing nitrogen gas or an oxygen scavenger in the airtight package containing the capsules, the amount of related substances produced from the fine powder of cepharanthine was reduced, and cepharanthine was stabilized. It can be seen that the characteristics can be maintained.
  • Example 4 The capsules obtained in Example 1 were placed in PTP (molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder). )) The packaged formulation was packed together with one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS SS-30) in an aluminum bag (manufactured by Sansan Nippon Co., Ltd.: AL-E).
  • PTP molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder).
  • the packaged formulation was packed together with one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.:
  • Example 5 The capsules obtained in Example 1 were placed in PTP (molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder). )) The packed preparation was packed together with one oxygen absorber (0.9 g (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name Ageless FX-30)) in an aluminum bag (manufactured by Seisan Nippon Co., Ltd.: AL-E).
  • PTP molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder).
  • the packed preparation was packed together with one oxygen absorber (0.9 g (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name Age
  • Example 6 The capsules obtained in Example 1 were put into PTP (formed sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM NS-3450, material: CPP, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: PTP AL CPP Iodine) )
  • PTP formed sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM NS-3450, material: CPP, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: PTP AL CPP Iodine
  • the packed formulation was packaged together with one oxygen absorber (1.5 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS ZM-1) in an aluminum bag (manufactured by Sansan Nippon Co., Ltd.: AL-E).
  • Example 7 The capsules obtained in Example 1 were subjected to PTP (molding sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSL-4603, material: PVC/PE/PVDC/PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name : Muji PTP (PVC yellow)) and one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS Z-30PKC) together with an aluminum bag (manufactured by Sansan Nihon Co., Ltd.: AL- E).
  • PTP molding sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM VSL-4603, material: PVC/PE/PVDC/PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name : Muji PTP (PVC yellow)
  • one oxygen absorber 1.3 g
  • Test example 5 For each of the samples of Examples 4 to 7, the ratio of cepharanthine-derived degradation products (related substances) before the start of storage and after storage for 3 days at 80° C. was measured using HPLC. As a result, as shown in Table 5, by enclosing nitrogen gas or an oxygen scavenger in the airtight package housing the capsules, the amount of related substances produced from the fine powder of cepharanthine was reduced, and cepharanthine was stabilized. It can be seen that the characteristics can be maintained. Table 6 shows the type of oxygen scavenger used, the amount of oxygen absorbed, and the range of application.
  • the oxygen absorption amount indicates the oxygen absorption amount (25°C) per oxygen scavenger, and the applicable range indicates the preferred range of water activity (AW). From Table 6, it can be seen that the type of oxygen scavenger does not affect the effect of the present invention.
  • PVC Polyvinyl chloride
  • CPP Unstretched polypropylene
  • PVDC Polyvinylidene chloride
  • PE Polyethylene
  • Production example 2 5.0 g of cepharanthine (D50: 133 ⁇ m) and 5.0 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 ⁇ m). 4.0 g of the obtained pulverized product and 16.0 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
  • Production example 3 5.0 g of cepharanthine (D50: 133 ⁇ m) and 5.0 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 ⁇ m). 2.0 g of the obtained pulverized product and 18.0 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
  • Production example 4 5.0 g of cepharanthine (D50: 133 ⁇ m) and 5.0 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 ⁇ m). 0.4 g of the obtained pulverized product and 19.6 g of lactose hydrate (D50: 134 ⁇ m, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
  • Examples 8-10 The powders obtained in Production Examples 2 to 4 were filled into No. 3 HPMC capsules (trade name: Vcaps TM Plus (white), sold by Lonza Japan Co., Ltd.) so that each capsule contained 100 mg, and 20 capsules were prepared.
  • the obtained capsules were PTP-packaged (formed sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM NS-3450, material: CPP, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: PTP AL CPP Yomuji).

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Abstract

The present invention addresses the problem of providing a new medicine for the prevention and/or treatment of COVID-19, which is an illness associated with SARS-CoV-2 infection.　The present invention relates to a medicinal product obtained by accommodating an encapsulated formulation containing (a) a cepharanthine powder having an average particle size of 0.5-10 µm and (b) lactose having an average particle size of 1-200 µm in hermetic packaging, wherein the interior of the hermetic packaging is filled with an inert gas and/or a deoxidizing agent.

Description

医薬品pharmaceuticals
　本発明は、セファランチンを含有する医薬品に関する。 The present invention relates to pharmaceuticals containing cepharanthine.
　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。
　これまでに、多数の既存薬物のスクリーニングがなされ、最近になって、セファランチンがＣＯＶＩＤ－１９の治療薬として期待されている（非特許文献１）。 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.
Many existing drugs have been screened so far, and recently, cepharanthine is expected as a therapeutic drug for COVID-19 (Non-Patent Document 1).
　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。 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.
　前記セファランチンは、現在、散剤及び錠剤の経口投与用製剤、並びに注射剤が用いられている。本発明者らは、ＳＡＲＳ－ＣｏＶ－２の感染抑制に効果的な薬物として考えられるセファランチンを最もＳＡＲＳ－ＣｏＶ－２が感染する部位に適用することを着想した。その結果、セファランチンを下気道に直接適用できる吸入剤とすることにより、当該目的が達成できることを見出し、また、セファランチンの粒子径を０．５～１０μｍとすることにより、下気道に直接セファランチンを効率よく供給可能な吸入剤が得られることを見出した。そして、さらに検討した結果、粒子径０．５～１０μｍのセファランチンと粒子径１～２００μｍの乳糖をカプセルに封入し、当該カプセルをさらに不活性ガス及び／又は脱酸素剤を封入した気密包装体に収容すれば、保存安定性に優れた、セファランチン含有カプセル剤を含む医薬品が得られることを見出し、本発明を完成した。 The cepharanthine is currently used as an oral dosage form of powder and tablets, as well as an injection. The present inventors came up with the idea of applying cepharanthine, which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most infected with SARS-CoV-2. As a result, it was found that the object can be achieved by making cepharanthine into an inhaler that can be directly applied to the lower respiratory tract. It has been found that a well deliverable inhalant is obtained. As a result of further investigation, cepharanthine with a particle size of 0.5 to 10 μm and lactose with a particle size of 1 to 200 μm are enclosed in a capsule, and the capsule is further enclosed in an airtight package containing an inert gas and / or an oxygen scavenger. The present inventors have found that a drug containing cepharanthine-containing capsules with excellent storage stability can be obtained by housing the container, and completed the present invention.
　すなわち、本発明は、次の発明［１］～［６］を提供するものである。
［１］（ａ）平均粒子径０．５～１０μｍのセファランチン及び（ｂ）平均粒子径１～２００μｍの乳糖を含有するカプセル剤を気密包装体に収容してなる医薬品であって、当該気密包装体内には不活性ガス及び／又は脱酸素剤が封入されてなる医薬品。
［２］カプセル剤中の成分（ａ）と成分（ｂ）の含有質量比（ａ／ｂ）が、０．００１～０．５である［１］記載の医薬品。
［３］カプセル剤が、吸入粉末用カプセル剤である［１］又は［２］記載の医薬品。
［４］１カプセル中の成分（ａ）の含有量が、０．０１～４０ｍｇである［１］～［３］のいずれかに記載の医薬品。
［５］カプセル剤中の成分（ｂ）が乳糖水和物である［１］～［４］のいずれかに記載の医薬品。
［６］不活性ガスが、窒素、ヘリウム、アルゴン、ネオン、クリプトン、ラドン、キセノン及び二酸化炭素から選ばれるガスである［１］～［５］のいずれかに記載の医薬品。 That is, the present invention provides the following inventions [1] to [6].
[1] A pharmaceutical product containing capsules containing (a) cepharanthine with an average particle size of 0.5 to 10 μm and (b) lactose with an average particle size of 1 to 200 μm in an airtight package, wherein the airtight package A drug in which an inert gas and/or an oxygen scavenger is enclosed in the body.
[2] The medicament according to [1], wherein the content mass ratio (a/b) of component (a) and component (b) in the capsule is 0.001 to 0.5.
[3] The drug according to [1] or [2], wherein the capsule is an inhalable powder capsule.
[4] The drug according to any one of [1] to [3], wherein the content of component (a) in one capsule is 0.01 to 40 mg.
[5] The drug according to any one of [1] to [4], wherein component (b) in the capsule is lactose hydrate.
[6] The drug according to any one of [1] to [5], wherein the inert gas is a gas selected from nitrogen, helium, argon, neon, krypton, radon, xenon and carbon dioxide.
　本発明の医薬品は、セファランチン微細粉末と乳糖を含有するカプセルが不活性ガス又は脱酸素剤が封入された気密包装体に収容されており、セファランチンの保存安定性に優れ、吸入粉末剤として使用すると、下気道にセファランチンを効率よく供給可能である。 The medicinal product of the present invention comprises capsules containing fine powder of cepharanthine and lactose and contained in an airtight package containing an inert gas or an oxygen scavenger. , can efficiently supply cepharanthine to the lower respiratory tract.
　本発明の医薬品の気密包装体に収容されてなるカプセル剤は、（ａ）粒子径０．５～１０μｍのセファランチン及び（ｂ）粒子径１～２００μｍの乳糖を含有する。 The capsule contained in the airtight package of the pharmaceutical of the present invention contains (a) cepharanthine with a particle size of 0.5-10 μm and (b) lactose with a particle size of 1-200 μm.
　本発明で用いる成分（ａ）のセファランチンは、化学名を６'，１２'－Ｄｉｍｅｔｈｏｘｙ－２，２'－ｄｉｍｅｔｈｙｌ－６，７－［ｍｅｔｈｙｌｅｎｅｂｉｓ（ｏｘｙ）］ｏｘｙａｃａｎｔｈａｎとする化学物質であり、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されうるアルカロイドの一種である。
　セファランチンは、放射線による白血球減少症、円形脱毛症・粃糠性脱毛症、滲出性中耳炎、マムシ咬傷の治療に用いられている。本発明のようにセファランチンを吸入剤とした場合には、これらの適応症に加えて、ＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び／又は治療薬として特に有用である。 Cepharanthine, the component (a) used in the present invention, is a chemical substance with the chemical name of 6′,12′-Dimethoxy-2,2′-dimethyl-6,7-[methylenebis(oxy)]oxycanthan. It is a kind of alkaloids that can be extracted from tsuzurafuji, koutou tsuzurafuji, lotus vine, and the like.
Cepharanthine is used to treat radiation-induced leukopenia, alopecia areata/alopecia pityriasis, otitis media with effusion, and viper bites. When cepharanthine is used as an inhalant as in the present invention, in addition to these indications, it is particularly useful as a SARS-CoV-2 infection inhibitor and a COVID-19 preventive and/or therapeutic agent.
　本発明において、セファランチンは化学合成されたものでも、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されたものでもいずれをも用いることができる。タマサキツヅラフジより抽出される場合は、セファランチンに加えて、イソテトランドリン、シクレアニン、ベルバミン等のセファランチン以外の他のアルカロイドをも含むタマサキツヅラフジ抽出物を用いることも可能である。セファランチンやタマサキツヅラフジ抽出物は市販品があり、購入して用いることが可能であり、また、タマサキツヅラフジ抽出物は公知の手法を用いることにより、タマサキツヅラフジから製造することができる。 In the present invention, cepharanthine can be used either chemically synthesized or extracted from Tamasakitsutsurafuji, Koutoutsutsurafuji, Lotus japonicum, and the like. In the case of extracting from Ceratophyllum japonicum, it is also possible to use an extract containing other alkaloids other than cepharanthine, such as isotetrandrine, cyclanine, and berbamine, in addition to cepharanthine. Cepharanthine and extracts of Rhubarb japonicum are commercially available and can be purchased and used, and the extract of Rhubarb japonicum can be produced from R. raffi by using a known method.
　本発明で用いるセファランチンを下気道（気管、気管支、肺臓）に適用するには、セファランチン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、１～８μｍとするのがより好ましく、２～８μｍとするのが更に好ましい。粒子径は、レーザー回折散乱式粒度分布測定法（Ｐａｒｔｉｃａ　ＬＡ－９５０Ｖ２：株式会社堀場製作所）により得られた累積頻度５０％径を意味する（以下、Ｄ５０と記載する場合がある）。この粒子径は、製造時の粉砕、篩過などによって調整することができる。 In order to apply the cepharanthine used in the present invention to the lower respiratory tract (trachea, bronchi, lungs), from the viewpoint of accessibility of the cepharanthine to the lower respiratory tract, the particle size is preferably from 0.5 to 10 μm, and from 1 to 10 μm. 8 μm is more preferable, and 2 to 8 μm is even more preferable. The particle diameter means the cumulative frequency 50% diameter obtained by a laser diffraction/scattering particle size distribution measurement method (Partica LA-950V2: Horiba, Ltd.) (hereinafter sometimes referred to as D50). The particle size can be adjusted by pulverization, sieving, or the like during production.
　１カプセル中のセファランチンの含有量は、１回投与量であるのが好ましく、０．０１～４０ｍｇであるのが好ましく、０．１～３０ｍｇであるのがより好ましく、１～２０ｍｇであるのが更に好ましい。
　カプセルは、１日につき１～３回程度に分けて、食前、食間、食後、就寝前等に１～８カプセル（好ましくは１～４カプセル、特に好ましくは１～２カプセル）服用することができる。 The content of cepharanthine in one capsule is preferably a single dose, preferably 0.01 to 40 mg, more preferably 0.1 to 30 mg, and preferably 1 to 20 mg. More preferred.
Capsules can be divided into about 1 to 3 times a day, and 1 to 8 capsules (preferably 1 to 4 capsules, particularly preferably 1 to 2 capsules) can be taken before meals, between meals, after meals, before bedtime, etc. .
　本発明で用いる成分（ｂ）の乳糖は、賦形剤である。乳糖としては、乳糖水和物を用いるのが好ましい。
　乳糖の粒子径は、セファランチンの下気道への到達性と保存安定性を考慮すると、１～２００μｍであるのが好ましく、１～１８０μｍであるのがより好ましい。この粒子径は、製造時の粉砕、篩過などによって調整することができる。 Lactose of component (b) used in the present invention is an excipient. As lactose, it is preferable to use lactose hydrate.
The particle size of lactose is preferably 1 to 200 μm, more preferably 1 to 180 μm, in consideration of accessibility to the lower respiratory tract and storage stability of cepharanthine. The particle size can be adjusted by pulverization, sieving, or the like during production.
　また、乳糖は、（ｂ１）粒子径１～５０μｍの微細乳糖と（ｂ２）粒子径５０～２００μｍの乳糖とを混合して用いるのが、セファランチンの下気道への到達性と保存安定性の観点でより好ましい。ここで、微細乳糖の粒子径は、１～４０μｍが好ましく、１～３０μｍがより好ましく、１～２０μｍが更に好ましい。粒子径５０～２００μｍの乳糖の粒子径は、７０～１８０μｍが好ましく、８０～１６０μｍがより好ましく、１００～１５０μｍが更に好ましい。また、微細乳糖と粒子径５０～２００μｍの乳糖との含有質量比（ｂ１／ｂ２）は、０．０００１～０．５が好ましく、０．００１～０．２がより好ましく、０．０１～０．１が更に好ましい。 In addition, lactose is used by mixing (b1) fine lactose with a particle size of 1 to 50 μm and (b2) lactose with a particle size of 50 to 200 μm, from the viewpoint of cepharanthin accessibility to the lower respiratory tract and storage stability. is more preferable. Here, the particle size of fine lactose is preferably 1 to 40 μm, more preferably 1 to 30 μm, even more preferably 1 to 20 μm. The particle size of lactose having a particle size of 50 to 200 μm is preferably 70 to 180 μm, more preferably 80 to 160 μm, even more preferably 100 to 150 μm. In addition, the content mass ratio (b1/b2) of fine lactose and lactose with a particle size of 50 to 200 μm is preferably 0.0001 to 0.5, more preferably 0.001 to 0.2, and 0.01 to 0. .1 is more preferred.
　成分（ａ）と成分（ｂ）の含有質量比（ａ／ｂ）は、セファランチンの下気道への到達性、保存安定性及び粉末吸入の容易性などの観点から、０．００１～０．５が好ましく、０．００５～０．２５がより好ましく、０．０１～０．１が更に好ましい。 The content mass ratio (a/b) of component (a) and component (b) is 0.001 to 0.5 from the viewpoint of accessibility of cepharanthine to the lower respiratory tract, storage stability and ease of powder inhalation. is preferred, 0.005 to 0.25 is more preferred, and 0.01 to 0.1 is even more preferred.
　本発明に用いられるカプセル剤には、前記成分（ａ）及び成分（ｂ）以外に、酢酸、リン酸、ホウ酸、クエン酸、酒石酸、乳酸、アスパラギン酸、ヒスチジン、アルギニン、リジン、グリシン、グルタミン酸、ε－アミノカプロン酸、硫酸及びそれらの薬学的に許容される塩、水酸化ナトリウム、塩酸等のｐＨ調整剤、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル等のパラベン類、ベンザルコニウム塩化物、またはクロロブタノール等の防腐剤、クロモグリク酸ナトリウム等の安定剤、カアトレジン、フェノール等の保存剤、亜硫酸水素ナトリウム、エデト酸ナトリウム、塩化ナトリウム、カルメロースナトリウム、キシリトール、グリセリン、クレアチニン、ステアリン酸マグネシウム、ニコチン酸アミド、マクロゴール（６００、４０００等）、トコフエロール及びその誘導体、亜硝酸ナトリウム、亜硫酸ナトリウム、アスコルビン酸等の安定化剤等、オレイン酸、精製オレイン酸、精製水等の基剤、無水エタノール等の可溶化剤、注射用水等の溶剤等などを含有させることもできるが、それらの含有量はカプセル内容物全量に対し、５質量％以下とするのが好ましく、３質量％以下とするのがより好ましく、２質量％以下とするのが更に好ましい。 Capsules used in the present invention contain acetic acid, phosphoric acid, boric acid, citric acid, tartaric acid, lactic acid, aspartic acid, histidine, arginine, lysine, glycine, glutamic acid, in addition to the above components (a) and (b). , ε-aminocaproic acid, sulfuric acid and their pharmaceutically acceptable salts, pH adjusters such as sodium hydroxide and hydrochloric acid, parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate, benzalkonium chloride, or Preservatives such as chlorobutanol, stabilizers such as sodium cromoglycate, preservatives such as kaatresin, phenol, sodium bisulfite, sodium edetate, sodium chloride, carmellose sodium, xylitol, glycerin, creatinine, magnesium stearate, nicotinic acid Stabilizers such as amide, macrogol (600, 4000, etc.), tocopherol and its derivatives, sodium nitrite, sodium sulfite, ascorbic acid, etc., bases such as oleic acid, purified oleic acid, purified water, absolute ethanol, etc. Solubilizers, solvents such as water for injection, etc. can be contained, but the content thereof is preferably 5% by mass or less, more preferably 3% by mass or less, relative to the total amount of capsule contents. It is preferably 2% by mass or less, and more preferably 2% by mass or less.
　本発明のカプセル剤は、硬カプセルであるのが好ましく、その剤皮としては、ゼラチン、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール共重合体、プルランなどが挙げられ、安定性の観点からヒドロキシプロピルメチルセルロースが特に好ましい。市販品としては、例えば、ＰＥＧ（マクロゴール）を配合した日本薬局方ゼラチンカプセル（クオリカプス株式会社）、ヒドロキシプロピルメチルセルロースを基剤とするクオリーＶTM（クオリカプス株式会社）やＶｃａｐｓTMＰｌｕｓ（ロンザジャパン株式会社）、ポリビニルアルコール共重合体を基剤とするＰＯＮＤＡＣTMカプセル（日新化成株式会社）、プルランを基剤とするＮＰｃａｐｓTM（ロンザジャパン株式会社）等が挙げられる。 The capsule of the present invention is preferably a hard capsule, and the shell thereof includes gelatin, hydroxypropylmethylcellulose, polyvinyl alcohol copolymer, pullulan and the like, and hydroxypropylmethylcellulose is particularly preferable from the viewpoint of stability. . Commercially available products include, for example, Japanese Pharmacopoeia gelatin capsules containing PEG (macrogol) (Qualicaps Co., Ltd.), Qualy V ™ (Qualicaps Co., Ltd.) and Vcaps ™ Plus (Lonza Japan Co., Ltd.) based on hydroxypropyl methylcellulose. company), polyvinyl alcohol copolymer-based PONDAC ™ capsules (Nissin Kasei Co., Ltd.), and pullulan-based NPcaps ™ (Lonza Japan Co., Ltd.).
　本発明のカプセル剤は、経口投与剤として使用することもできるが、吸入粉末カプセル剤として使用するのが、セファランチンを下気道に到達させる観点から好ましい。本発明のカプセル剤の使用に際しては、吸入投与のために適切な器具又は装置を使用すればよい。 Although the capsule of the present invention can be used as an orally administered drug, it is preferably used as an inhalation powder capsule from the viewpoint of allowing cepharanthine to reach the lower respiratory tract. When using the capsules of the present invention, a device or device suitable for inhalation administration may be used.
　吸入粉末カプセル剤の吸入投与のための器具の具体例としては、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。本発明の吸入粉末用カプセル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。 A specific example of a device for inhalation administration of an inhalation powder capsule is a dry powder inhaler (hereinafter abbreviated as DPI). Devices commonly used as DPIs can be used for the inhalable powder capsules of the present invention. For example, devices include Monohaler, Handyhaler, Breezhaler, Flowcaps, and the like.
　前記カプセル剤は、さらに、不活性ガス及び／又は脱酸素剤が封入された気密包装体に収容して医薬品として供給する。
　本発明において「気密包装体」とは、通常の取扱い、運搬又は保存等の状態において、固体及び液体の包装体外からの実質的な侵入を抑制し得る包装を意味し、第十八改正日本薬局方　通則に定義される「気密容器」及び「密封容器」を包含する概念である。当該包装体としては、定形、不定形のいずれのものも用いることができ、具体的には例えば、ビン包装、ＳＰ（Ｓｔｒｉｐ　Ｐａｃｋａｇｅ）包装、ＰＴＰ（Ｐｒｅｓｓ　Ｔｈｒｏｕｇｈ　Ｐａｃｋａｇｅ）包装、ピロー包装、スティック包装等が挙げられる。本発明においては、さらにこれらを複数組み合わせたものであってもよく、具体的には例えば、前記カプセル剤をまずＰＴＰ包装にて包装し、これをさらにピロー包装にて包装する形態が挙げられる。 The capsules are further housed in an airtight package containing an inert gas and/or an oxygen scavenger and supplied as a pharmaceutical product.
In the present invention, the "airtight package" means a package that can substantially prevent solid and liquid from entering from the outside of the package under normal handling, transportation, storage, etc. This concept includes "airtight container" and "sealed container" defined in the General Rules. As the packaging body, both fixed and irregular shapes can be used, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, and the like. is mentioned. In the present invention, more than one of these may be combined, and a specific example thereof is a form in which the capsules are first packaged by PTP packaging and then further packaged by pillow packaging.
　気密包装体の包装材料（素材）としては、通常防湿性を発揮し得るものであれば特に限定されず、医薬品や食品の分野で、水分に弱い内容物の防湿等を目的として用いられる材料を適宜用いることができる。
　ビン包装に用いられるビン本体の材料としては例えば、ガラス、プラスチック（ポリエステル、ポリエチレン（低密度（ＬＤＰＥ）、高密度（ＨＤＰＥ）を含む）、ポリカーボネート、ポリスチレン、ポリプロピレン等）、金属（アルミニウム）等が挙げられる。また、栓や蓋の材料としては例えば、プラスチック（ポリエステル、ポリエチレン、ポリカーボネート、ポリスチレン、ポリプロピレン等）、金属（アルミニウム）等が挙げられる。ビン包装するに際しては、例えば、前記カプセル剤を、市販のビン内に適当な数量格納し、次いで、適当な栓や蓋で封をすればよい。なお、ビンは、格納するカプセル剤の数量に応じた大きさのものを適宜選択すればよく、ビンの容量としては、例えば、１０～５００ｍＬ程度であり、１４～４００ｍＬが好ましく、２４～３５０ｍＬがより好ましい。ビン包装の材料としては、ポリエチレン、ポリプロピレンが好ましく、低密度ポリエチレン（ＬＤＰＥ）、高密度ポリエチレン（ＨＤＰＥ）がより好ましく、高密度ポリエチレン（ＨＤＰＥ）が特に好ましい。 The packaging material (material) for the airtight package is not particularly limited as long as it can normally exhibit moisture resistance, and materials used for the purpose of moisture-proofing contents that are vulnerable to moisture in the fields of pharmaceuticals and foods are used. It can be used as appropriate.
Examples of the material of the bottle body used for bottle packaging include glass, plastic (polyester, polyethylene (including low density (LDPE) and high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metal (aluminum), and the like. mentioned. Materials for the stopper and lid include, for example, plastics (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), and the like. For packaging in bottles, for example, a suitable number of capsules may be stored in a commercially available bottle and then sealed with a suitable stopper or lid. The size of the bottle may be appropriately selected according to the number of capsules to be stored. more preferred. As a material for bottle packaging, polyethylene and polypropylene are preferable, low density polyethylene (LDPE) and high density polyethylene (HDPE) are more preferable, and high density polyethylene (HDPE) is particularly preferable.
　また、ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装等に用いられる包装材料としては例えば、二軸延伸ポリプロピレン（ＯＰＰ）、二軸延伸ポリエステル（ＰＥＴ）、グルコース変性ＰＥＴ（ＰＥＴ－Ｇ）、二軸延伸ナイロン（ＯＮｙ、ＰＡ）、セロハン、紙、低密度ポリエチレン（ＬＤＰＥ）、直鎖状低密度ポリエチレン（Ｌ－ＬＤＰＥ）、エチレン－酢酸ビニル共重合体（ＥＶＡ）、無延伸ポリプロピレン（ＣＰＰ、ＩＰＰ）、アイオノマー樹脂（ＩＯ）、エチレン－メタクリル酸共重合体（ＥＭＡＡ）、ポリアクリロニトリル（ＰＡＮ）、二軸延伸ポリ塩化ビニリデン（ＰＶＤＣ）、エチレン－ビニルアルコール共重合樹脂（ＥＶＯＨ）、ポリ塩化ビニル（ＰＶＣ）、環状ポリオレフィン（ＣＯＣ）、無延伸ナイロン（ＣＮｙ）、ポリカーボネート（ＰＣ）、ポリスチレン（ＰＳ）、硬質塩化ビニル（ＶＳＣ）等の樹脂や、アルミニウム箔（ＡＬ）のような金属箔等が挙げられ、これらの２種以上を適宜組み合わせた多層構造としてもよい。斯かる多層構造としては例えば、ＰＶＣとＰＶＤＣを積層したもの（ＰＶＣ／ＰＶＤＣ。以下、同様に省略して表記する。）、ＰＶＣ／ＰＶＤＣ／ＰＥ／ＰＶＣ、ＰＶＣ／ＰＶＤＣ／ＰＥ／ＰＶＤＣ／ＰＶＣ、ＣＰＰ／ＣＯＣ／ＣＰＰ、ＰＶＣ／ＡＬ、ＣＰＰ／ＡＬ、ＣＰＰ／ＣＰＰ／ＣＰＰ等が挙げられる。斯かる多層構造を形成する方法としては、押出しラミネート、ドライラミネート、共押出しラミネート、サーマルラミネート、ウェットラミネート、ノンソルベントラミネート、ヒートラミネート等の公知のラミネート方法が挙げられる。ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装等に用いられる包装材料としては、ポリ塩化ビニル、アルミニウム箔が好ましい。 Examples of packaging materials used for SP packaging, PTP packaging, pillow packaging and stick packaging include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose-modified PET (PET-G), biaxial Oriented nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP) , ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC ), cyclic polyolefin (COC), unstretched nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid vinyl chloride (VSC) and other resins, and metal foils such as aluminum foil (AL). , a multi-layer structure in which two or more of these are appropriately combined. Examples of such a multilayer structure include a laminate of PVC and PVDC (PVC/PVDC, hereinafter abbreviated in the same way), PVC/PVDC/PE/PVC, PVC/PVDC/PE/PVDC/PVC, CPP/COC/CPP, PVC/AL, CPP/AL, CPP/CPP/CPP and the like. Methods for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, co-extrusion lamination, thermal lamination, wet lamination, non-solvent lamination and heat lamination. Polyvinyl chloride and aluminum foil are preferable as packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like.
　ＰＴＰ包装の形態としては、公知の方法で樹脂シート等に所望数成形したポケットに、前記カプセル剤を１個又は１投与単位ずつ格納し、次いでアルミニウム箔等の金属箔を構成材料とするシートをフタ材として用いて蓋をすることが挙げられる。なお、ポケットを形成するシートとしてもアルミニウム箔を構成材料とするシートを用いた、いわゆる両面アルミＰＴＰ包装としてもよい。本発明においては、防湿性を高める観点から、ＰＴＰアルミニウム箔を構成材料とするシート等を用いて、カプセル剤を１個又は１投与単位ずつ包装することが挙げられる。本発明においては、アルミニウム箔を構成材料とするシートを用いるのが好ましい。 As for the form of PTP packaging, a desired number of the capsules are stored in pockets formed on a resin sheet or the like by a known method, and then a sheet made of metal foil such as aluminum foil is used as a constituent material. For example, it can be used as a lid material to form a lid. A so-called double-sided aluminum PTP package using a sheet made of aluminum foil as a constituent material of the pocket forming sheet may also be used. In the present invention, from the viewpoint of enhancing moisture resistance, a sheet or the like having PTP aluminum foil as a constituent material is used to package capsules one by one or by one dosage unit. In the present invention, it is preferable to use a sheet whose constituent material is aluminum foil.
　なお、本発明の医薬品における、カプセル剤の包装体内部での占有率（容積率）は、包装体がビン包装の場合、通常、２５～９０％であり、２８～８０％が好ましく、３０～７０％がより好ましい。また、包装体がＳＰ包装、ＰＴＰ包装、ピロー包装、スティック包装の場合、通常３０～９８％であり、４０～９５％が好ましく、４５～９３％がより好ましく、５０～９０％が特に好ましい。なお、この場合において、占有率とは、包装体内部の容積に対するカプセル剤の占有率を意味するものであり、包装体内部に格納したカプセル剤の破損防止のための詰め物や中栓等は、空間占有率を算出するに際して考慮されるものではない。 In the pharmaceutical product of the present invention, the occupancy rate (volume ratio) of the capsule inside the package is usually 25 to 90%, preferably 28 to 80%, and 30 to 90% when the package is bottle packaging. 70% is more preferred. When the package is SP packaging, PTP packaging, pillow packaging or stick packaging, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. In this case, the occupancy ratio means the occupancy ratio of the capsule to the internal volume of the package. It is not taken into account when calculating space occupancy.
　本発明においては、気密包装体として市販の包装体をそのまま用いてもよく、また市販の包装材料を加工して用いてもよい。このような市販品としては例えば、ビン包装の包装体としては、Ｚ－シリーズ（以上、阪神化成工業社製）等が挙げられる。また、ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装用の包装材料としては、スミライトＶＳＳ、スミライトＶＳＬ、スミライトＮＳ、スミライトＦＣＬ（以上、住友ベークライト社製）、ＴＡＳシリーズ（大成化工社製）、ＰＴＰ用ビニホイル、ＰＴＰ用スーパーホイル（以上、三菱樹脂社製）、ニッパクアルミ箔（日本製箔社製）、アルミ箔銀無地（大和化学工業社製）等が挙げられる。 In the present invention, a commercially available package may be used as it is as an airtight package, or a commercially available packaging material may be processed and used. Examples of such commercially available products include the Z-series (manufactured by Hanshin Kasei Kogyo Co., Ltd.), etc., as packaging bodies for bottle packaging. Packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include SUMILITE VSS, SUMILITE VSL, SUMILITE NS, SUMILITE FCL (manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Taisei Kako Co., Ltd.), and PTP. Vinyl Foil for PTP, Super Foil for PTP (manufactured by Mitsubishi Plastics Co., Ltd.), Nippaku Aluminum Foil (manufactured by Nippon Foil Co., Ltd.), Aluminum Foil Silver Plain (manufactured by Daiwa Chemical Industry Co., Ltd.), and the like.
　本発明の医薬品において、前記カプセル剤を収容した気密包装体内には不活性ガス及び／又は脱酸素剤が封入される。不活性ガス及び／又は脱酸素剤を封入することにより、カプセル内のセファランチン粉末の保存安定性が向上する。具体的には、セファランチンの類縁物質の生成が抑制される。 In the pharmaceutical product of the present invention, an inert gas and/or an oxygen scavenger are enclosed in the airtight package housing the capsule. The storage stability of the cepharanthine powder in the capsule is improved by enclosing an inert gas and/or an oxygen scavenger. Specifically, the production of cepharanthine-related substances is suppressed.
　不活性ガスとしては、窒素、ヘリウム、アルゴン、ネオン、クリプトン、ラドン、キセノン、二酸化炭素などが挙げられる。このうち、入手容易性、安全性などの点から窒素ガス、アルゴンガス等がより好ましい。不活性ガスの封入は、気密包装体内の空気を不活性ガスに置換することにより、酸素を極力減少させればよい。 Inert gases include nitrogen, helium, argon, neon, krypton, radon, xenon, and carbon dioxide. Among these, nitrogen gas, argon gas, and the like are more preferable from the viewpoint of availability, safety, and the like. Encapsulation of inert gas can be achieved by replacing the air in the airtight package with inert gas to reduce oxygen as much as possible.
　脱酸素剤としては、鉄粉などの金属粉末、第一鉄塩、亜二チオン酸塩、亜硫酸塩、ハロゲン化金属などの無機物を主体とするもの、アスコルビン酸、エリソルビン酸、それらの塩、ヒドロキノンやカテコールなどのポリフェノールなどの有機化合物を主体とするものなど種々のものが知られており、毒性がなく且つ酸素吸収性能に優れるものであればいずれも使用できる。また、脱酸素剤には自力反応型と水分依存型があるが、本発明ではそれらのいずれも使用できる。市販のものとしては、三菱ガス化学社製の「エージレス」（商品名）のＳタイプ、ＳＳタイプ、Ｚタイプ、ＦＸタイプ、ＺＭタイプ、ＳＡタイプ、ＧＬタイプ、「ファーマキープ」（商品名）などが知られており、エージレスは本発明において好適に使用できる。また、脱酸素剤の市販品としては、大江化学工業社製の「タモツ」（商品名）のＶＸタイプ、Ｄタイプ、「酸素カット」（商品名）のＧＤタイプなども使用できる。
　また、脱酸素剤としては、酸素吸収量（脱酸素剤１個当たりの酸素吸収量：ｍＬ）が１０ｍＬ以上のものが好ましく、２０ｍＬ以上のものがより好ましく、２５ｍＬ以上のものがさらに好ましい。また、脱酸素剤としては、水分活性値（ＡＷ）が高い食品の脱酸素剤として用いられるものであるのが好ましく、食品への適用範囲（水分活性値）が、０．３以上のものが好ましい。 Examples of oxygen scavengers include metal powders such as iron powder, inorganic substances such as ferrous salts, dithionites, sulfites, and metal halides, ascorbic acid, erythorbic acid, salts thereof, and hydroquinone. Various substances are known, such as those mainly composed of organic compounds such as polyphenols such as catechol and catechol. In addition, there are self-reacting type and moisture-dependent type oxygen scavengers, and both of them can be used in the present invention. Commercially available products include "Ageless" (trade name) S type, SS type, Z type, FX type, ZM type, SA type, GL type, and "Pharma Keep" (trade name) manufactured by Mitsubishi Gas Chemical Co., Ltd. is known, and Ageless is suitable for use in the present invention. In addition, as commercially available oxygen scavengers, “Tamotsu” (trade name) VX type, D type, and “Oxygen cut” (trade name) GD type manufactured by Ohe Kagaku Kogyo Co., Ltd. can also be used.
The oxygen absorber preferably has an oxygen absorption amount (oxygen absorption amount per oxygen absorber: mL) of 10 mL or more, more preferably 20 mL or more, and even more preferably 25 mL or more. Also, the oxygen absorber is preferably used as an oxygen absorber for foods with a high water activity value (AW), and the range of application to foods (water activity value) is 0.3 or more. preferable.
　本発明においては、例えば、前記カプセル剤をまずＰＴＰ包装にて包装し、これをさらにピロー包装にて包装する形態が挙げられ、このピロー包装とＰＴＰ包装の空間に不活性ガス及び／又は脱酸素剤を封入するのが好ましい。 In the present invention, for example, the capsule is first packaged in PTP packaging and then further packaged in pillow packaging. Encapsulation of the agent is preferred.
　本発明の医薬品は、セファランチンの適応症である円形脱毛症・粃糠性脱毛症、滲出性中耳炎、マムシ咬傷に加えて、ＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び／又は治療薬として用いることができる。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、セファランチンとして１日１～２０ｍｇの範囲が挙げられる。また、本発明の医薬品をＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び／又は治療薬として用いる場合、ネルフィナビルなどの抗ＨＩＶ剤と併用することもできる。 In addition to alopecia areata, alopecia pityriasis, otitis media with effusion, and viper bites, which are indications of cepharanthine, the pharmaceutical of the present invention is a SARS-CoV-2 infection inhibitor, prevention of COVID-19 and / or It can be used as a therapeutic agent. The dose varies depending on the patient's body weight, age, sex, symptoms, etc., but is usually in the range of 1 to 20 mg of cepharanthine per day for adults. In addition, when the drug of the present invention is used as a SARS-CoV-2 infection inhibitor or a COVID-19 prophylactic and/or therapeutic drug, it can be used in combination with an anti-HIV agent such as nelfinavir.
　次に実施例を挙げて本発明をさらに詳細に説明するが、本発明は、これら実施例に制限されるものではない。 The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.
参考例１
　ジェットミルで粉砕したセファランチン（粒子径：１．２μｍ：レーザー回折法により測定）１．５ｇに乳糖水和物９８．５ｇを添加し、ハイフレックスグラル（深江パウテック（株）製、ＨＦ－ＧＳ－２Ｊ）で混合した。得られた粉末０．１ｇをカプセルに充填して、吸入粉末剤を製造した。 Reference example 1
98.5 g of lactose hydrate was added to 1.5 g of cepharanthine pulverized by a jet mill (particle size: 1.2 μm: measured by laser diffraction method), and Hiflex Gral (Fukae Powtech Co., Ltd., HF-GS- 2J). 0.1 g of the resulting powder was filled into capsules to produce an inhalable powder.
参考比較例１
　未粉砕のセファランチン（粒子径：５０μｍ：レーザー回折法により測定）１．５ｇに乳糖水和物９８．５ｇを添加し、ハイフレックスグラル（深江パウテック（株）製、ＨＦ－ＧＳ－２Ｊ）で混合した。得られた粉末０．１ｇをカプセルに充填して、吸入粉末剤を製造した。 Reference Comparative Example 1
98.5 g of lactose hydrate was added to 1.5 g of unground cepharanthine (particle size: 50 μm: measured by laser diffraction method) and mixed with Hiflex Gral (manufactured by Fukae Powtec Co., Ltd., HF-GS-2J). bottom. 0.1 g of the resulting powder was filled into capsules to produce an inhalable powder.
試験例１
　参考例１及び参考比較例１で得た吸入粉末剤について、デバイスとしてモノヘラーを用いて、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）を測定した。結果を表１に示す。
（１）Ｓｔａｇｅ２表示率（％）
　吸入剤のＩｎ　ｖｉｔｒｏ評価装置であるＴｗｉｎ　Ｉｍｐｉｎｇｅｒを用いて、気道到達率であるＳｔａｇｅ２表示率を求めた。
（２）微粒子量（ＦＰＤ）（％）
　日本薬局方　第十七改正第二追補の吸入剤の空気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。 Test example 1
For the inhalable powders obtained in Reference Example 1 and Reference Comparative Example 1, the Stage 2 display rate (%) and the fine particle content (FPD) (%) were measured using a monohaler as a device. Table 1 shows the results.
(1) Stage2 display rate (%)
Using a Twin Impinger, which is an in vitro evaluation device for inhalants, the Stage 2 display rate, which is the airway reach rate, was determined.
(2) Fine particle amount (FPD) (%)
Evaluation was performed using a multi-stage liquid impinger of Apparatus 1 in accordance with the aerodynamic particle size measurement method for inhalants of the Japanese Pharmacopoeia 17th Edition, Second Supplement.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１の結果から明らかなように、参考例１の吸入粉末剤は、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）が３０％程度と高く、肺深部までセファランチンを到達させることが可能と考えられた。
　一方、参考比較例１のセファランチン未粉砕の場合は、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）が３％程度と低く、肺深部までセファランチンを到達させることは困難と考えられた。 As is clear from the results in Table 1, the inhalation powder of Reference Example 1 has a Stage 2 display rate (%) and a fine particle content (FPD) (%) as high as about 30%, and cepharanthine can reach the deep lung. considered possible.
On the other hand, in the case of non-pulverized cepharanthine in Reference Comparative Example 1, the Stage 2 display rate (%) and the fine particle content (FPD) (%) were as low as about 3%, and it was considered difficult for cepharanthine to reach the deep lung. .
参考例２
［サンプル１］
　セファランチン（Ｄ５０：１３３μｍ）２ｇをガラス瓶（２Ｋ規格瓶）に入れ、サンプル１とした。
［サンプル２］
　ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇをガラス瓶（２Ｋ規格瓶）に入れ、サンプル２とした。
［サンプル３］
　ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇと乳糖水和物１８ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０）を混合し、ガラス瓶（２Ｋ規格瓶）に入れ、サンプル３とした。
［サンプル４］
　ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇと乳糖水和物１８ｇ（Ｄ５０：８．１μｍ、商品名：ＩｎｈａＬａｃTM４００）を混合し、ガラス瓶（２Ｋ規格瓶）に入れ、サンプル４とした。 Reference example 2
[Sample 1]
2 g of cepharanthine (D50: 133 μm) was placed in a glass bottle (2K standard bottle) to obtain sample 1.
[Sample 2]
2 g of cepharanthine (D50: 3.5 μm) pulverized by a jet mill was placed in a glass bottle (2K standard bottle) to obtain sample 2.
[Sample 3]
2 g of cepharanthine (D50: 3.5 μm) pulverized by a jet mill and 18 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120) were mixed and placed in a glass bottle (2K standard bottle) to obtain sample 3.
[Sample 4]
2 g of cepharanthine (D50: 3.5 μm) pulverized with a jet mill and 18 g of lactose hydrate (D50: 8.1 μm, trade name: InhaLac TM 400) were mixed, placed in a glass bottle (2K standard bottle), and sample 4 and bottom.
試験例２
　上記各種サンプルにつき、保存開始前及び８０℃３日間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣ装置を用いて測定した。具体的には、セファランチンの類縁物質の割合を、セファランチン及びその類縁物質に由来する総ピーク面積に対する面積百分率（％）として測定した。
　そして、得られた各種サンプルについての保存開始前及び８０℃３日間保存後のセファランチンの類縁物質の割合（％）より、以下の式に従い、各種サンプルについてのセファランチン由来の分解物の増加率（％）を算出した。
　セファランチン由来の分解物の増加率（％）＝（８０℃３日間保存後のセファランチンの類縁物質の割合（％））－（保存開始前のセファランチンの類縁物質の割合（％）） Test example 2
For each of the above samples, the ratio of cepharanthine-derived decomposition products (related substances) before the start of storage and after storage for 3 days at 80° C. was measured using an HPLC device. Specifically, the proportion of cepharanthine-related substances was measured as an area percentage (%) with respect to the total peak area derived from cepharanthine and its related substances.
Then, from the ratio (%) of cepharanthine related substances before the start of storage and after storage for 3 days at 80 ° C. for various samples obtained, according to the following formula, the increase rate (%) of degradation products derived from cepharanthine for each sample ) was calculated.
Increase rate (%) of decomposition products derived from cepharanthine = (percentage (%) of cepharanthine-related substances after storage at 80°C for 3 days) - (percentage (%) of cepharanthine-related substances before the start of storage)
＜分解物の測定＞
　分解物の測定は、以下の条件にて液体クロマトグラフ法により定量した。
検出器：紫外吸光光度計（測定波長：２８４ｎｍ）
カラム温度：４０℃付近の一定温度
カラム：液体クロマトグラフ用オクタデシルシリル化シリカゲル（４．６ｍｍ×１５ｃｍ、φ５μｍ）
移動相：アセトニトリル／薄めたトリエチルアミン（１→２０００）混液（１：１） <Measurement of decomposition products>
Decomposition products were quantified by liquid chromatography under the following conditions.
Detector: UV absorption photometer (measurement wavelength: 284 nm)
Column temperature: Constant temperature around 40° C. Column: Octadecylsilylated silica gel for liquid chromatography (4.6 mm×15 cm, φ5 μm)
Mobile phase: acetonitrile/diluted triethylamine (1→2000) mixture (1:1)
　得られた結果を表２に示す。
　表２より、セファランチンは、微粉末とすることにより、保存安定性が低下することが判明した。セファランチンは、乳糖と混合しても、保存安定性が低下した。 Table 2 shows the results obtained.
From Table 2, it was found that the storage stability of cepharanthine decreased when it was finely powdered. Cepharanthine showed reduced storage stability even when mixed with lactose.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
製造例１
　ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇ、乳糖水和物１７．２６ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）、及び乳糖水和物０．７４ｇ（Ｄ５０：８．１μｍ、商品名：ＩｎｈａＬａｃTM４００、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を混合し、粉末を得た。 Production example 1
2 g of cepharanthine (D50: 3.5 μm) pulverized by a jet mill, 17.26 g of lactose hydrate (D50: 134 μm, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG), and lactose hydrate 0.74 g (D50: 8.1 μm, trade name: InhaLac ™ 400, sales company: MEGGLE GmbH & CO. KG) was mixed to obtain a powder.
実施例１
　製造例１で得た粉末を１カプセル当たり１００ｍｇとなるように３号ＨＰＭＣカプセル（商品名：ＶｃａｐｓTMＰｌｕｓ（白色）、販売会社：ロンザジャパン株式会社）に充填し２００カプセル調製した。
　得られた５カプセルをガラス瓶（２Ｋ規格瓶）に入れ、医薬製剤を製した。 Example 1
The powder obtained in Production Example 1 was filled in No. 3 HPMC capsules (trade name: Vcaps ™ Plus (white), sales company: Lonza Japan Co., Ltd.) so that each capsule contained 100 mg, and 200 capsules were prepared.
Five capsules thus obtained were placed in a glass bottle (2K standard bottle) to prepare a pharmaceutical preparation.
比較例１
　製造例１で得た粉末１００ｍｇをガラス瓶（２Ｋ規格瓶）に入れ、医薬製剤を製した。 Comparative example 1
100 mg of the powder obtained in Production Example 1 was placed in a glass bottle (2K standard bottle) to prepare a pharmaceutical preparation.
試験例３
　上記各種サンプルにつき、保存開始前及び６０℃２週間保存後のセファランチン由来の類縁物質の割合を、ＨＰＬＣ装置を用いて測定した。 Test example 3
For each of the above samples, the ratio of cepharanthine-derived related substances before the start of storage and after storage at 60° C. for 2 weeks was measured using an HPLC device.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表３より、（ａ）平均粒子径０．５～１０μｍのセファランチンと、（ｂ）平均粒子径１～２００μｍの乳糖とを、カプセル中に封入することにより、保存安定性が向上することがわかった。 From Table 3, it can be seen that storage stability is improved by encapsulating (a) cepharanthine having an average particle size of 0.5 to 10 μm and (b) lactose having an average particle size of 1 to 200 μm. rice field.
実施例２
　前記実施例１で得た５カプセルをガラス瓶（７Ｋ規格瓶）に入れ、ガラス瓶中の空気を窒素に置換し医薬品を製した。 Example 2
The 5 capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle), and the air in the glass bottle was replaced with nitrogen to prepare a drug.
実施例３
　前記実施例１で得た５カプセル及び脱酸素剤１個（１２．７ｇ）（三菱ガス化学株式会社製：商品名　エージレスＳＳ－３００）をガラス瓶（７Ｋ規格瓶）に入れ、医薬品を製した。 Example 3
Five capsules obtained in Example 1 and one deoxidant (12.7 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS SS-300) were placed in a glass bottle (7K standard bottle) to prepare a drug.
比較例２
　前記実施例１で得た５カプセルをガラス瓶（７Ｋ規格瓶）に入れ、医薬品を製した。 Comparative example 2
Five capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle) to prepare a drug.
試験例４
　前記実施例２，３及び比較例２の各サンプルにつき、保存開始前及び６０℃４週間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣ装置を用いて測定した。
　その結果、表４に示すように、カプセル剤を収容した気密包装体の内部に窒素ガス又は脱酸素剤を封入することにより、セファランチン微粉末由来の類縁物質の生成量が減少し、セファランチンの安定性が保持できることがわかる。 Test example 4
For each of the samples of Examples 2 and 3 and Comparative Example 2, the ratio of cepharanthine-derived decomposition products (related substances) before the start of storage and after storage at 60° C. for 4 weeks was measured using an HPLC device.
As a result, as shown in Table 4, by enclosing nitrogen gas or an oxygen scavenger in the airtight package containing the capsules, the amount of related substances produced from the fine powder of cepharanthine was reduced, and cepharanthine was stabilized. It can be seen that the characteristics can be maintained.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
実施例４
　前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＳ－１２０２、材質：ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（１．３ｇ）（三菱ガス化学株式会社製：商品名　エージレスＳＳ－３０）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。 Example 4
The capsules obtained in Example 1 were placed in PTP (molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite ™ VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder). )) The packaged formulation was packed together with one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS SS-30) in an aluminum bag (manufactured by Sansan Nippon Co., Ltd.: AL-E).
実施例５
　前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＳ－１２０２、材質：ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（０．９ｇ（三菱ガス化学株式会社製：商品名　エージレスＦＸ－３０））と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。 Example 5
The capsules obtained in Example 1 were placed in PTP (molded sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite ™ VSS-1202, material: PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: Muji PTP (PVC powder). )) The packed preparation was packed together with one oxygen absorber (0.9 g (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name Ageless FX-30)) in an aluminum bag (manufactured by Seisan Nippon Co., Ltd.: AL-E).
実施例６
　前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＮＳ－３４５０、材質：ＣＰＰ、アルミ箔…東洋アルミニウム株式会社製、商品名：ＰＴＰ　ＡＬ　ＣＰＰヨウ　ムジ）包装した製剤を脱酸素剤１個（１．５ｇ）（三菱ガス化学株式会社製：商品名　エージレスＺＭ－１）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。 Example 6
The capsules obtained in Example 1 were put into PTP (formed sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM NS-3450, material: CPP, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: PTP AL CPP Iodine) ) The packed formulation was packaged together with one oxygen absorber (1.5 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS ZM-1) in an aluminum bag (manufactured by Sansan Nippon Co., Ltd.: AL-E).
実施例７
　前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＬ－４６０３、材質：ＰＶＣ／ＰＥ／ＰＶＤＣ／ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（１．３ｇ）（三菱ガス化学株式会社製：商品名　エージレスＺ－３０ＰＫＣ）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。 Example 7
The capsules obtained in Example 1 were subjected to PTP (molding sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite ™ VSL-4603, material: PVC/PE/PVDC/PVC, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name : Muji PTP (PVC yellow)) and one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS Z-30PKC) together with an aluminum bag (manufactured by Sansan Nihon Co., Ltd.: AL- E).
試験例５
　前記実施例４～７の各サンプルにつき、保存開始前及び８０℃３日間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣを用いて測定した。
　その結果、表５に示すように、カプセル剤を収容した気密包装体の内部に窒素ガス又は脱酸素剤を封入することにより、セファランチン微粉末由来の類縁物質の生成量が減少し、セファランチンの安定性が保持できることがわかる。
　なお、用いた脱酸素剤のタイプ、酸素吸収量及び適用範囲を表６に示す。表６中、酸素吸収量は脱酸素剤１個当たりの酸素吸収量（２５度）を示し、適用範囲は好ましい水分活性（ＡＷ）の範囲を示す。表６より、脱酸素剤のタイプは本発明の効果に影響しないことがわかる。 Test example 5
For each of the samples of Examples 4 to 7, the ratio of cepharanthine-derived degradation products (related substances) before the start of storage and after storage for 3 days at 80° C. was measured using HPLC.
As a result, as shown in Table 5, by enclosing nitrogen gas or an oxygen scavenger in the airtight package housing the capsules, the amount of related substances produced from the fine powder of cepharanthine was reduced, and cepharanthine was stabilized. It can be seen that the characteristics can be maintained.
Table 6 shows the type of oxygen scavenger used, the amount of oxygen absorbed, and the range of application. In Table 6, the oxygen absorption amount indicates the oxygen absorption amount (25°C) per oxygen scavenger, and the applicable range indicates the preferred range of water activity (AW). From Table 6, it can be seen that the type of oxygen scavenger does not affect the effect of the present invention.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
ＰＶＣ：ポリ塩化ビニル
ＣＰＰ：無延伸ポリプロピレン
ＰＶＤＣ：ポリ塩化ビニリデン
ＰＥ：ポリエチレン PVC: Polyvinyl chloride CPP: Unstretched polypropylene PVDC: Polyvinylidene chloride PE: Polyethylene
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
製造例２
　ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品４．０ｇと乳糖水和物１６．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を混合し、粉末を得た。 Production example 2
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 μm). 4.0 g of the obtained pulverized product and 16.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
製造例３
　ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品２．０ｇと乳糖水和物１８．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を混合し、粉末を得た。 Production example 3
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 μm). 2.0 g of the obtained pulverized product and 18.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
製造例４
　ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品０．４ｇと乳糖水和物１９．６ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ　ＧｍｂＨ　＆　ＣＯ．ＫＧ）を混合し、粉末を得た。 Production example 4
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac TM 120, sales company: MEGGLE GmbH & CO. KG) were pulverized in a jet mill to obtain a pulverized product. (average particle size: 2.6 μm). 0.4 g of the obtained pulverized product and 19.6 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sales company: MEGGLE GmbH & Co. KG) were mixed to obtain a powder.
実施例８～１０
　前記製造例２～４で得た粉末を１カプセル当たり１００ｍｇとなるように３号ＨＰＭＣカプセル（商品名：ＶｃａｐｓTMＰｌｕｓ（白色）、販売会社：ロンザジャパン株式会社）に充填し２０カプセル調製した。
　得られたカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＮＳ－３４５０、材質：ＣＰＰ、アルミ箔…東洋アルミニウム株式会社製、商品名：ＰＴＰ　ＡＬ　ＣＰＰヨウ　ムジ）包装した製剤（２個×５個カプセルを１シートとし、２シート）を脱酸素剤１個（１．５ｇ）（三菱ガス化学株式会社製：商品名　エージレスＺＭ－１）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）（１６ｃｍ×１０ｃｍ）に包装し、実施例８～１０とした。 Examples 8-10
The powders obtained in Production Examples 2 to 4 were filled into No. 3 HPMC capsules (trade name: Vcaps ™ Plus (white), sold by Lonza Japan Co., Ltd.) so that each capsule contained 100 mg, and 20 capsules were prepared.
The obtained capsules were PTP-packaged (formed sheet: manufactured by Sumitomo Bakelite Co., Ltd., trade name: Sumilite TM NS-3450, material: CPP, aluminum foil: manufactured by Toyo Aluminum Co., Ltd., trade name: PTP AL CPP Yomuji). (2 sheets x 5 capsules, 2 sheets), 1 oxygen absorber (1.5 g) (manufactured by Mitsubishi Gas Chemical Co., Ltd.: trade name AGELESS ZM-1) and an aluminum bag (Production Nipponsha Co., Ltd.) Product: AL-E) (16 cm x 10 cm) and packaged as Examples 8-10.

Claims (6)

  1. 　（ａ）平均粒子径０．５～１０μｍのセファランチン及び（ｂ）平均粒子径１～２００μｍの乳糖を含有するカプセル剤を気密包装体に収容してなる医薬品であって、当該気密包装体内には不活性ガス及び／又は脱酸素剤が封入されてなる医薬品。 (a) cepharanthine with an average particle size of 0.5 to 10 μm and (b) lactose with an average particle size of 1 to 200 μm are contained in an airtight package, and the airtight package contains A pharmaceutical containing an inert gas and/or an oxygen scavenger.
  2. 　カプセル剤中の成分（ａ）と成分（ｂ）の含有質量比（ａ／ｂ）が、０．００１～０．５である請求項１記載の医薬品。 The pharmaceutical product according to claim 1, wherein the content mass ratio (a/b) of component (a) and component (b) in the capsule is 0.001 to 0.5.
  3. 　カプセル剤が、吸入粉末用カプセル剤である請求項１又は２記載の医薬品。 The pharmaceutical product according to claim 1 or 2, wherein the capsule is an inhalable powder capsule.
  4. 　１カプセル中の成分（ａ）の含有量が、０．０１～４０ｍｇである請求項１～３のいずれか１項記載の医薬品。 The pharmaceutical according to any one of claims 1 to 3, wherein the content of component (a) in one capsule is 0.01 to 40 mg.
  5. カプセル剤中の成分（ｂ）が乳糖水和物である請求項１～４のいずれか１項記載の医薬品。 The pharmaceutical product according to any one of claims 1 to 4, wherein component (b) in the capsule is lactose hydrate.
  6. 　不活性ガスが、窒素、ヘリウム、アルゴン、ネオン、クリプトン、ラドン、キセノン及び二酸化炭素から選ばれるガスである請求項１～５のいずれか１項記載の医薬品。 The drug according to any one of claims 1 to 5, wherein the inert gas is a gas selected from nitrogen, helium, argon, neon, krypton, radon, xenon and carbon dioxide.
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JPH11180873A (en) * 1997-12-22 1999-07-06 Kaken Shoyaku Kk Nf-kappa b activity inhibitor
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JP2012524716A (en) * 2009-04-24 2012-10-18 イシューティカ ピーティーワイ リミテッド Fabrication of nanoparticles encapsulated at a high volume ratio
JP2013522371A (en) * 2010-03-23 2013-06-13 シガ・テクノロジーズ・インコーポレーテッド ST-246 polymorphic form and preparation method
JP2017530149A (en) * 2014-10-01 2017-10-12 サン ファーマシューティカル インダストリーズ リミテッドＳｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉｅｓ Ｌｔｄ． Low dose oral isotretinoin pharmaceutical composition
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JPH09227565A (en) * 1996-02-23 1997-09-02 Kaken Shiyouyaku Kk Wound healing agent
JPH11180873A (en) * 1997-12-22 1999-07-06 Kaken Shoyaku Kk Nf-kappa b activity inhibitor
JP2012524716A (en) * 2009-04-24 2012-10-18 イシューティカ ピーティーワイ リミテッド Fabrication of nanoparticles encapsulated at a high volume ratio
JP2013522371A (en) * 2010-03-23 2013-06-13 シガ・テクノロジーズ・インコーポレーテッド ST-246 polymorphic form and preparation method
KR20120045122A (en) * 2010-10-29 2012-05-09 비알엔사이언스 주식회사 Composition for preventing and treating bone diseases comprising arthritis
JP2017530149A (en) * 2014-10-01 2017-10-12 サン ファーマシューティカル インダストリーズ リミテッドＳｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉｅｓ Ｌｔｄ． Low dose oral isotretinoin pharmaceutical composition
WO2021230340A1 (en) * 2020-05-14 2021-11-18 興和株式会社 Novel inhalant

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