WO2023080189A1 - Produit médicamenteux - Google Patents

Produit médicamenteux 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
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WIPO (PCT)
Prior art keywords
cepharanthine
capsule
particle size
packaging
capsules
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PCT/JP2022/041114
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English (en)
Japanese (ja)
Inventor
英輝 小澤
隆宏 森
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興和株式会社
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Publication of WO2023080189A1 publication Critical patent/WO2023080189A1/fr

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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
    • A61K31/4738—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

L'invention a pour objet de fournir un nouveau médicament destiné à la prévention et/ou au traitement du ＣＯＶＩＤ－１９, et de troubles liés à une infection au ＳＡＲＳ－ＣｏＶ－２. 　Plus précisément, l'invention concerne un produit médicamenteux dans lequel une capsule comprenant (a) une poudre de cépharanthine de diamètre particulaire moyen compris entre ０,５ et １０μｍ et (b) un lactose de diamètre particulaire moyen compris entre １ et ２００μｍ, est admise dans un emballage hermétique, et un gaz inerte et/ou un désoxygénant est encapsulé à l'intérieur de l'emballage hermétique.
PCT/JP2022/041114 2021-11-04 2022-11-04 Produit médicamenteux WO2023080189A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09227565A (ja) * 1996-02-23 1997-09-02 Kaken Shiyouyaku Kk 創傷治療剤
JPH11180873A (ja) * 1997-12-22 1999-07-06 Kaken Shoyaku Kk ＮＦ−κＢ活性阻害剤
KR20120045122A (ko) * 2010-10-29 2012-05-09 비알엔사이언스 주식회사 관절염을 포함한 골 질환 예방 및 치료용 조성물
JP2012524716A (ja) * 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 高体積率で封入されるナノ粒子の作製
JP2013522371A (ja) * 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の多形型および調製方法
JP2017530149A (ja) * 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． 低用量経口イソトレチノイン医薬組成物
WO2021230340A1 (fr) * 2020-05-14 2021-11-18 興和株式会社 Nouveau produit à inhaler

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09227565A (ja) * 1996-02-23 1997-09-02 Kaken Shiyouyaku Kk 創傷治療剤
JPH11180873A (ja) * 1997-12-22 1999-07-06 Kaken Shoyaku Kk ＮＦ−κＢ活性阻害剤
JP2012524716A (ja) * 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 高体積率で封入されるナノ粒子の作製
JP2013522371A (ja) * 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の多形型および調製方法
KR20120045122A (ko) * 2010-10-29 2012-05-09 비알엔사이언스 주식회사 관절염을 포함한 골 질환 예방 및 치료용 조성물
JP2017530149A (ja) * 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． 低用量経口イソトレチノイン医薬組成物
WO2021230340A1 (fr) * 2020-05-14 2021-11-18 興和株式会社 Nouveau produit à inhaler

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