WO2017022814A1 - Composition for nebulizers - Google Patents

Composition for nebulizers Download PDF

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Publication number
WO2017022814A1
WO2017022814A1 PCT/JP2016/072885 JP2016072885W WO2017022814A1 WO 2017022814 A1 WO2017022814 A1 WO 2017022814A1 JP 2016072885 W JP2016072885 W JP 2016072885W WO 2017022814 A1 WO2017022814 A1 WO 2017022814A1
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WIPO (PCT)
Prior art keywords
nebulizer
composition
weight
active ingredient
content
Prior art date
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PCT/JP2016/072885
Other languages
French (fr)
Japanese (ja)
Inventor
泰寛 堤
和博 井上
道子 公文
敦俊 伊藤
一志 石塚
Original Assignee
第一三共株式会社
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.)
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Application filed by 第一三共株式会社 filed Critical 第一三共株式会社
Priority to KR1020177029766A priority Critical patent/KR20180030399A/en
Priority to CN201680045861.9A priority patent/CN107847482A/en
Priority to JP2017533115A priority patent/JP6908523B2/en
Publication of WO2017022814A1 publication Critical patent/WO2017022814A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a nebulizer composition for treating or preventing influenza virus infection, comprising as an active ingredient laninamivir octanoate hydrate having neuraminidase inhibitory activity or a pharmacologically acceptable salt thereof.
  • Laninamivir octanoate hydrate exhibits an excellent neuraminidase inhibitory action and is administered to the recipient's respiratory tract, causing it to stay in the recipient's respiratory tissues (upper respiratory tract, lungs, etc.), causing influenza virus infection (Patent Documents 1 to 3). *
  • laninamivir octanoate hydrate exhibits anti-influenza action by retention in the recipient's respiratory tissue, it causes parenteral route to reach the respiratory tissue by parenteral route. Therefore, a dry powder inhalation preparation has been disclosed as a dosage form for administering laninamivir octanoate hydrate by the parenteral route (Patent Document 4).
  • a dry powder inhalation preparation is prepared by storing a powder formulation for inhalation in a container such as a capsule, a blister, a reservoir in a device, a dosing disk, or the like. Inhale from device.
  • a container such as a capsule, a blister, a reservoir in a device, a dosing disk, or the like.
  • a powder formulation for inhalation in a container
  • those with difficulty in spontaneous breathing such as children, the elderly, and patients with reduced respiratory function, may not be able to properly handle dry powder inhalation preparations and may be difficult to inhale a sufficient amount of drug.
  • a person with difficulty in spontaneous breathing may have difficulty in securing a sufficient amount of inspiration. For such a person with difficulty in spontaneous breathing, it is desired to develop a suitable administration method and dosage form so that a sufficient amount of drug can stably reach the respiratory tissue.
  • an administration method using a nebulizer is known as an administration method that can be surely inhaled by children.
  • administration by a nebulizer is performed as an administration method that can be surely inhaled by children and those with difficulty in spontaneous breathing.
  • anti-influenza drugs especially neuraminidase inhibitors, oseltamivir phosphate (trade name Tamiflu, Patent Document 5), zanamivir hydrate (trade name Relenza, Patent Document 6) and peramivir hydrate (trade name Rapiacta, Patent Document 7) ) Is commercially available.
  • neuraminidase inhibitors especially neuraminidase inhibitors, oseltamivir phosphate (trade name Tamiflu, Patent Document 5), zanamivir hydrate (trade name Relenza, Patent Document 6) and peramivir hydrate (trade name Rapiacta, Patent Document 7) )
  • Tamiflu is a preparation for oral administration and is commercially available as a capsule or dry syrup preparation.
  • Lapiactor is an injection for intravenous infusion. Since these drugs are not administered by inhalation, it is impossible to select a nebulizer as an administration means.
  • Zanamivir (trade name Relenza) is a formulation for inhalation, but requires continuous administration for multiple days. For most patients who do not have a nebulizer, administering Relenza with a nebulizer is burdensome to the body because it requires a visit to each dose.
  • Japanese Patent No. 3209946 U.S. Pat. No. 6,340,702, European Patent No. 823428
  • Japanese Patent No. 3920041 U.S. Pat. No. 6,844,363, European Patent No. 1,277,750
  • Japanese Patent No. 4205314 International Publication No. 2001/080892 pamphlet
  • Japanese Patent No. 5697199 Patent of International Publication No. 2010/074113
  • International Publication No. 96/26933 Pamphlet WO91 / 16320 pamphlet Japanese Patent No. 4102022 US Pat. No. 6,503,745, European Patent No. 1040094
  • the present inventors have intensively studied for many years on drugs for treating / preventing influenza virus infection.
  • laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is used as an active ingredient, and the recipient's respiratory tissues (upper respiratory tract, lungs, etc.) are selected by appropriate selection of the composition and appropriate adjustment of the particle size. ) (E.g., excellent respiratory reachability), low irritation at the time of inhalation, and excellent physical stability.
  • the headline and the present invention were completed.
  • the present invention [1] A composition for nebulizers containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersant and an osmotic pressure regulator, [2] The nebulizer composition according to [1] above, containing 1 to 20% by weight of laninamivir octanoate hydrate, [3] The nebulizer composition according to the above [1] or [2], containing 3 to 10% by weight of laninamivir octanoate hydrate, [4] The particle size of 50% by weight in the laser diffraction / scattering particle size distribution measurement method of laninamivir octanoate hydrate is 5.0 ⁇ m or less and 90% by weight in the laser diffraction / scattering particle size distribution measurement method. The composition for a nebulizer according to any one of the above [1] to [3], wherein the particle diameter of [5] The
  • composition for nebulizers as described, [12] In the above [12], the content of polyoxyethylene sorbitan monolaurate is 0.038 to 0.2% by weight, and the content of sorbitan monolaurate is 0.1 to 0.2% by weight.
  • the composition for nebulizers as described, [13] The nebulizer composition according to any one of [1] to [12], wherein the osmotic pressure regulator is sodium chloride or lactose hydrate.
  • the freeze-dried preparation according to the above [17], [19] The lyophilized preparation according to the above [17], wherein the dispersant is tyloxapol, [20]
  • a method of spraying and inhaling the nebulizer composition according to any one of [1] to [16] using a nebulizer [25] any one of [17] to [23] The lyophilized preparation according to the item, dispersed in a suspension liquid to make an inhalation solution, and sprayed using a nebulizer for inhalation, [26] A preventive or therapeutic agent for influenza virus infection comprising the nebulizer composition according to any one of [1] to [16], [27] A preventive or therapeutic agent for influenza virus infection comprising an inhalation solution prepared by dispersing the lyophilized preparation according to any one of [17] to [23] in a suspension liquid, [28] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 40 to 320 mg in terms of anhydride per administration.
  • the nebulizer composition according to any one of the above [1] to [16], [29] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 80 mg in terms of anhydride per administration
  • the nebulizer composition according to any one of [1] to [16], [30] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 160 mg in terms of anhydride per administration
  • the nebulizer composition according to any one of [1] to [16], [31] The nebulizer composition according to any one of [1] to [16] and [28] to [30] is applied to a human respiratory organ before the onset of influenza virus.
  • a method for preventing influenza virus infection by spraying and inhaling [32]
  • the nebulizer composition according to any one of [1] to [16] and [28] to [30] is applied to a human respiratory organ at the onset of influenza virus.
  • the lyophilized preparation according to any one of [17] to [23] is dispersed in a suspension liquid to form an inhalation solution, and the nebulizer is used in a human respiratory tract before the onset of influenza virus.
  • the lyophilized preparation according to any one of [17] to [23] is dispersed in a suspension liquid to form an inhalation solution, and the nebulizer is used in a human respiratory tract when influenza virus develops. This is a method for treating influenza virus infection by nebulizing and inhaling.
  • the active ingredient of the nebulizer composition of the present invention is laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof.
  • Laninamivir octanoate hydrate has the following formulas (I) and (II):
  • the laninamivir octanoic acid ester hydrate represented by the above formulas (I) and (II) has a guanidino group and a carboxyl group in the molecule, it binds to a pharmacologically non-toxic acid or base.
  • a top acceptable salt can be formed.
  • the “pharmacologically acceptable salt” of laninamivir octanoate ester hydrate refers to such a salt.
  • Examples of the “pharmacologically acceptable salt” include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, Inorganic acid salts such as sulfate and phosphate; Alkane sulfonate such as methane sulfonate, ethane sulfonate and trifluoromethane sulfonate; benzene sulfonate and p-toluene sulfonate Aryl sulfonates; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate, maleate; glycine, lysine, arginine, ornithine, glutamate, asparagine Amino acid salts such as acid salts; alkali metal salts such as lithium salts, sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts
  • the laninamivir octanoic acid ester hydrate and its pharmacologically acceptable salt may absorb water by being left in the atmosphere or mixed with water to form a hydrate.
  • the hydrate of laninamivir octanoate ester or a pharmacologically acceptable salt thereof refers to such a hydrate.
  • Laninamivir octanoic acid ester hydrate and pharmacologically acceptable salts thereof have an asymmetric carbon in the molecule and have stereoisomers (including enantiomers and diastereomers). These stereoisomers and mixtures in arbitrary proportions (including racemates) are included in the laninamivir octanoic acid ester hydrate and pharmacologically acceptable salts thereof which are the active ingredients of the present invention.
  • the particle size of laninamivir octanoic acid ester hydrate or pharmacologically acceptable salt thereof contained in the nebulizer composition of the present invention is preferably 50% by weight of particles in the laser diffraction scattering type particle size distribution measurement method.
  • the diameter is 5.0 ⁇ m or less and the 90% by weight particle size in the laser diffraction / scattering particle size distribution measurement method is 12.0 ⁇ m or less, more preferably 50% by weight in the laser diffraction / scattering particle size distribution measurement method.
  • the active ingredient of the present invention is particularly excellent in inhalability, has high respiratory reachability and can pass through the pharynx to reach the deep lung, resulting in high and long-lasting anti-influenza Demonstrate activity.
  • the nebulizer composition of the present invention is an inhalation solution for nebulizers that further contains a dispersant and an osmotic pressure regulator in addition to the above active ingredients.
  • the dispersant is a compound added to disperse a compound contained in the nebulizer composition, particularly an active ingredient, uniformly in the liquid.
  • a surfactant or an emulsifier can be used as the dispersant.
  • the dispersant for example, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan tristearate (Tween 65), or One selected from the group consisting of polysorbate of polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (span 20), tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa) or What combined 2 types can be illustrated.
  • Tween 20 polyoxyethylene sorbitan monolaurate
  • Tween 60 polyoxyethylene sorbitan monostearate
  • Tween 65 polyoxyethylene sorbitan tristearate
  • CMCNa sodium carboxymethylcellulose
  • polyoxyethylene sorbitan monolaurate Tween 20
  • sorbitan monolaurate Span 20
  • tyloxapol sorbitan monolaurate
  • HPMC hydroxypropylmethylcellulose
  • Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) can be used in combination.
  • tyloxapol is more preferable, or a combination of two types of polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20).
  • tyloxapol is more preferable.
  • the nebulizer composition of the present invention contains an osmotic pressure regulator.
  • the osmotic pressure adjusting agent is a compound added to adjust the osmotic pressure of the nebulizer composition of the present invention.
  • the nebulizer of the present invention is selected.
  • the osmotic pressure of the composition for use can be made equal to the osmotic pressure of bodily fluids, specifically bodily fluids in the oral cavity and respiratory tissues (upper respiratory tract, lungs, etc.).
  • the nebulizer composition of the present invention isotonic with body fluids, the irritation at the time of inhalation of the nebulizer composition of the present invention can be reduced, and the active ingredient of the present invention that can reach the respiratory tissue
  • the amount fine particle amount, FPD
  • osmotic pressure regulator examples include sodium chloride or lactose hydrate.
  • sodium chloride is preferred.
  • Saline can be used as an aqueous solution of sodium chloride.
  • the volume of the nebulizer composition of the present invention per inhalation with a nebulizer is preferably 2 to 8 ml, particularly preferably 2 ml.
  • the content of the active ingredient is preferably 1 to 20% by weight, more preferably 3 to 10% by weight. Within this range, a sufficient amount of the active ingredient can be supplied to the respiratory tissues (upper respiratory tract, lungs, etc.) of the recipient who has inhaled the nebulizer composition of the present invention.
  • the content of the dispersant varies depending on the compound used.
  • the content is preferably 0.01 to 1% by weight, more preferably. 0.05 to 0.5% by weight.
  • hydroxypropylmethylcellulose HPMC
  • the content is preferably 0.1 to 1% by weight.
  • polyoxyethylene sorbitan monolaurate Tween 20
  • the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
  • the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
  • polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) may be used in combination.
  • the content is preferably from 0.038 to polyoxyethylene sorbitan monolaurate (Tween 20).
  • 0.2 wt% and sorbitan monolaurate (span 20) is 0.1 to 0.2 wt%.
  • the active ingredient exhibits excellent dispersibility in the nebulizer composition of the present invention.
  • the content of the osmotic pressure regulator varies depending on the compound used.
  • sodium chloride is preferably 0.45 to 1.8% by weight in the nebulizer composition of the present invention
  • lactose hydrate is preferably 5 to 10% by weight.
  • the freeze-dried preparation of the present invention contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further contains a dispersant or further an osmotic pressure regulator.
  • the nebulizer composition of the present invention is obtained by dispersing the lyophilized preparation of the present invention with a suspension liquid.
  • the dispersant contained in the freeze-dried preparation of the present invention is the same as the dispersant contained in the nebulizer composition of the present invention.
  • the osmotic pressure regulator that can be contained in the freeze-dried preparation of the present invention is also the same as the osmotic pressure regulator contained in the nebulizer composition of the present invention.
  • the freeze-dried preparation of the present invention contains an active ingredient, a dispersant, and an osmotic pressure regulator
  • the content of the active ingredient contained in the freeze-dried preparation is 55 to 95% by weight
  • the inclusion of the dispersant The rate is 1.0 to 10.0% by weight
  • the content of the osmotic pressure regulator is 4 to 35% by weight.
  • the lyophilized preparation of the present invention two kinds of dispersants can be used in combination.
  • the effective content contained in the lyophilized formulation The content of the component is 60 to 90% by weight, the content of polyoxyethylene sorbitan monolaurate (Tween 20) is 0.5 to 5.0% by weight, and the content of sorbitan monolaurate (span 20) The ratio is 1.5 to 5.0% by weight, and the content of sodium chloride is preferably 8.0 to 30% by weight.
  • the lyophilized preparation of the present invention may contain only an active ingredient and a tyloxapol as a dispersant.
  • a tyloxapol as a dispersant.
  • the content of the active ingredient contained in the freeze-dried preparation is 93.0 to 98.5% by weight, and the content of the dispersant is 1.5 to 7.0% by weight. is there.
  • nebulizer composition of the present invention prepared from the freeze-dried preparation of the present invention is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
  • a nebulizer preferably a jet nebulizer (also referred to as a compressor nebulizer).
  • the nebulizer composition of the present invention has excellent dispersibility of the active ingredient in the composition, so even if it is a recipient who is difficult to breathe spontaneously, such as children, elderly people, and those with reduced respiratory function.
  • the active ingredient can efficiently reach the respiratory tissues (upper airways, lungs, etc.) of the person.
  • the active ingredient in which the active ingredient has a specific particle size distribution, the active ingredient can reach the recipient's respiratory tissue, particularly the upper respiratory tract and lungs, and therefore has a high and long-lasting anti-tumor properties. Influenza activity is maintained.
  • nebulizer composition of the present invention is an isotonic solution when administered to a recipient, irritation to respiratory tissue is reduced.
  • the freeze-dried preparation of the present invention is excellent in physical stability, and the nebulizer composition of the present invention prepared using the freeze-dried preparation stored at normal temperature and pressure for 6 months or more exhibits excellent sprayability. .
  • the laninamivir octanoic acid ester hydrate which is an active ingredient of the nebulizer composition of the present invention, or a pharmacologically acceptable salt thereof is disclosed in WO2008 / 126943 or WO2013 / 089168. It can be produced according to the method disclosed in the pamphlet or a method analogous thereto.
  • the effective component of the nebulizer composition of the present invention has a particle size of 50% by weight or less of the active component measured by the laser diffraction / scattering particle size distribution measurement method of 5.0 ⁇ m or less, and the laser diffraction / scattering particle size.
  • the particle diameter of 90% by weight of the active ingredient is preferably 12.0 ⁇ m or less by the distribution measurement method.
  • the particle diameter of 50% by weight of the active ingredient according to the laser diffraction / scattering particle size distribution measurement method is 3.2 ⁇ m or less
  • the particle diameter of 90% by weight of the active ingredient according to the laser diffraction / scattering particle size distribution measurement method is 8 It is more preferable that it is 0.0 ⁇ m or less.
  • the laninamivir octanoic acid ester hydrate having such a particle size, or a pharmacologically acceptable salt thereof is a method disclosed in International Publication No. 2008/126943 pamphlet or International Publication No. 2013/089168 pamphlet. Or it can manufacture according to the method according to it.
  • the lyophilized preparation of the present invention can be produced by the method described below.
  • the active ingredient produced as a predetermined particle diameter by the method disclosed in the above-mentioned international publication or a method according thereto is made into fine particles by a dry pulverization method such as a jet mill.
  • a dry pulverization method such as a jet mill.
  • the finely divided active ingredient is combined with the solution obtained by dissolving the dispersant and the osmotic pressure regulator, and the active ingredient fine particles are mixed with a homogenizer such as Hiscotron or a high-pressure homogenizer such as emulflex or microfluidizer. Disperse, then fill the resulting mixture into a container and lyophilize to form a lyophilized formulation.
  • the finely divided active ingredient is combined with a dispersant dissolved in purified water, and the active ingredient fine particles are dispersed by a homogenizer such as Hiscotron or a high-pressure homogenizer such as emulflex or microfluidizer.
  • a homogenizer such as Hiscotron or a high-pressure homogenizer such as emulflex or microfluidizer.
  • the resulting suspension is then filled into a container and lyophilized to form a lyophilized formulation.
  • This method is a production method used when a freeze-dried preparation contains only an active ingredient and a dispersant.
  • the lyophilized preparation of the present invention thus produced is prepared as a nebulizer composition by adding and dispersing a suspension liquid in an enclosed container.
  • the suspension liquid is preferably purified water.
  • an aqueous solution of an osmotic pressure regulator is used as the suspension liquid.
  • an aqueous solution of sodium chloride or physiological saline include an aqueous solution of sodium chloride or physiological saline.
  • the nebulizer composition of the present invention thus produced is a suspension-like aqueous liquid preparation.
  • nebulizer composition of the present invention is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
  • a nebulizer preferably a jet nebulizer (also referred to as a compressor nebulizer).
  • the dose of the nebulizer composition of the present invention is preferably 40 to 320 mg, more preferably 80 to 160 mg, and particularly preferably 160 mg per administration of laninamivir octanoate in terms of anhydride.
  • the dosage of the composition for nebulizer of the present invention is, for example, 80 mg, 160 mg, 240 mg, 320 mg, preferably 80 mg per one administration of laninamivir octanoic acid ester in terms of anhydride. 160 mg, particularly preferably 160 mg.
  • the nebulizer composition of the present invention When the nebulizer composition of the present invention is administered as a preventive agent for influenza virus infection, it is intermittently administered to human respiratory tissue before the onset of influenza virus infection. For each dose, the above dose is inhaled.
  • the administration interval is, for example, 5 to 10 days or 1 week.
  • before onset means a state in which no influenza symptoms are observed regardless of the presence or absence of viral infection.
  • administration before the onset of influenza symptoms may be a preventive administration, regardless of whether or not the patient has been infected with influenza virus.
  • the administration time of the prophylactic agent of the present invention includes administration before onset regardless of the presence or absence of infection.
  • the above dose is inhaled into a human respiratory tissue at the onset of influenza virus infection by a single administration.
  • influenza virus is infected and subjective symptoms such as fever are observed.
  • a nebulizer which is an inhalation device
  • a recipient who does not have such a device repeats the nebulizer composition of the present invention because administration is completed once. There is no need to go to the hospital, and the recipient's visit to the hospital is less burdensome. Since the treatment is completed with a single administration, only the laninamivir octanoate hydrate is the only neuraminidase inhibitor currently on the market that can be combined with a nebulizer as a product.
  • Examples 1 to 3 Manufacture of a composition for nebulizer Crystals of laninamivir octanoate hydrate produced according to the production method described in International Publication No. 2008/126943 (hereinafter referred to as an active ingredient).
  • the mixture was pulverized by a jet mill method (supersonic jet pulverizer (type PJM-100SP), Nippon Pneumatic Industry Co., Ltd.) to obtain a pulverized product having a particle size distribution shown in Table 1.
  • a homogenizer Hiscotron (model :): a combination of a predetermined amount of hydroxypropylmethylcellulose as a dispersant, lactose hydrate or sodium chloride dissolved in purified water as an osmotic pressure regulator, and a predetermined amount of active ingredient.
  • NS-50 pre-dispersed by Nissin Medical Science Co., Ltd., and then dispersed by a high-pressure homogenizer (microfluidizer (model: M-110EH), Powrec Co., Ltd.).
  • a suspension-like composition was obtained.
  • the resulting composition is shown in Table 2.
  • * 1 Indicates the weight of the active ingredient as an anhydride.
  • Example 4 Manufacture of a composition for a nebulizer
  • a predetermined amount of polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (span 20) and sodium chloride were dissolved in purified water as a dispersant.
  • Pre-dispersed with a homogenizer (Hiscotron) (NS-50, Nissin Medical Science Instrument Co., Ltd.), and then dispersed with a microfluidizer (M-110EH, Paulek Co., Ltd.)
  • a homogenizer Hiscotron
  • M-110EH microfluidizer
  • * 1 Indicates the weight of the active ingredient as an anhydride.
  • composition containing only a dispersant As a dispersant, polyoxyethylene sorbitan monooleate (Tween 80) and / or sodium carboxymethylcellulose (CMCNa) is dissolved in purified water, and a predetermined amount of the pulverized active ingredient And pre-dispersed with a homogenizer (Hiscotron (model: NS-50), Nissin Medical Science Mfg. Co., Ltd.), followed by a high-pressure homogenizer (microfluidizer (model: M-110EH), POWREC Co., Ltd.) Dispersion was performed to obtain a suspension-like composition. The obtained composition is shown in Table 5.
  • a homogenizer Hiscotron (model: NS-50), Nissin Medical Science Mfg. Co., Ltd.
  • microfluidizer model: M-110EH
  • * 1 Indicates the weight of the active ingredient as an anhydride.
  • Example 6 Preparation of nebulizer composition and lyophilized preparation
  • a predetermined amount of tyloxapol as a dispersant and a predetermined amount of sodium chloride dissolved in purified water as an osmotic pressure regulator are mixed together.
  • a stirrer MAZELA Z (model: Z-1100), EYELA
  • a high-pressure homogenizer microfluidizer (model: H-110EH), POWREC Co., Ltd.
  • a suspension-like composition of Example 6 was obtained.
  • the obtained composition was lyophilized using a lyophilizer (Trimaster II A-04, Kyowa Vacuum) to obtain a lyophilized preparation of Example 7.
  • Table 6 shows the composition of the obtained preparation.
  • Examples 8 to 14 Production of lyophilized preparation for nebulizer A predetermined amount of tyloxapol as a dispersing agent was dissolved in purified water, combined with a predetermined amount of pulverized active ingredient, and a stirrer (MAZELA Z (model: Z-1100) , EYELA), and then dispersed with a high-pressure homogenizer (pressure homogenizer (model: LAB1000), SMT Co., Ltd.). Lyophilized to obtain freeze-dried preparations of Examples 8-14. Table 7 shows the composition of the obtained freeze-dried preparation.
  • Example 15 to 22 Preparation of composition for nebulizer
  • Purified water was added to the lyophilized preparation obtained in Example 7, and physiological saline was added to the lyophilized preparation obtained in Examples 8 to 14, and dispersed.
  • the nebulizer compositions of Examples 15 to 22 were obtained. Table 8 shows the obtained composition.
  • Examples 23 to 25 Preparation of compositions having different active ingredient contents Of the lyophilized preparation of Example 9 dispersed in 4 mL of physiological saline, 2 mL was injected into a nebulizer to obtain a preparation containing 40 mg of the active ingredient. Two of the lyophilized preparations of Example 23 and Example 9 dispersed in 1 mL of physiological saline and injected into a nebulizer were combined in Example 24, and the lyophilized preparation of Example 9 was added to physiological saline 0. An inhalation liquid for nebulizer was obtained as Example 25, in which four dispersed in 5 mL were poured into a nebulizer. The amount of active ingredient indicates the weight as an anhydride. Table 9 shows the obtained composition.
  • Example 26 to 28 Production of lyophilized preparation for nebulizer A predetermined amount of tyloxapol as a dispersant was dissolved in purified water, and the jet mill method (supersonic jet crusher (model PJM-100SP), Nippon Pneumatic Industry Co., Ltd.) ) And pre-dispersed with a stirrer (seal mixer (model: RC-60G5-2S), Magneo Giken), followed by high-pressure homogenizer (pressure homogenizer (model: R5-10.38) The resulting mixture was freeze-dried using a freeze dryer (freeze vacuum dryer (model DFB3055-2BS-ST / CIP), ULVAC, Inc.), and Examples 26 to 28 were dispersed. A freeze-dried preparation was obtained. Table 10 shows the composition of the obtained freeze-dried preparation.
  • Example 29 to 35 Preparation of composition with different active ingredient content
  • 2 mL was injected into the nebulizer and the composition for nebulizer containing 40 mg of the active ingredient
  • the freeze-dried preparation of Example 26 was dispersed in 2 mL of physiological saline and injected into a nebulizer to prepare a nebulizer composition containing 80 mg of the active ingredient in Example 30
  • Two of the freeze-dried preparations of Example 26 dispersed in 1 mL of physiological saline were poured into a nebulizer and the nebulizer composition containing 160 mg of the active ingredient was used as the freeze-dried examples 31 and 26.
  • nebulizer composition containing 240 mg of the active ingredient Three of the preparations dispersed in 1 mL of physiological saline were combined and injected into a nebulizer to prepare a nebulizer composition containing 240 mg of the active ingredient.
  • the lyophilized preparations of Example 32 and Example 26 were added to 1 mL of physiological saline.
  • Four of those dispersed in (1) were poured into a nebulizer, and the nebulizer compositions containing 320 mg of the active ingredient were dispersed in 2 ml of physiological saline in Example 33 and Example 27, and the nebulizer was dispersed in the nebulizer.
  • the nebulizer composition containing 80 mg of the active ingredient was injected into the dried preparations of Example 34 and Example 28 as physiological saline.
  • the active ingredient was as in Example 35 to those with nebulizer composition containing 160 mg.
  • the amount of active ingredient indicates the weight as an anhydride.
  • the obtained composition is shown in Table 11.
  • * 1 Represents the weight of the active ingredient as an anhydride in a vial.
  • * 2 Represents the weight of the active ingredient as an anhydride.
  • This method uses a device that classifies drug particles sucked into the impactor through a pump from an inhaler.
  • the aspirated medicine reaches any one of 10 parts (mouthpiece adapter, induction port, stages 1 to 7, micro-orifice collector (MOC)) constituting the impactor according to the particle diameter. Large particles such as agglomerates are collected in the mouthpiece adapter and induction port.
  • drug particles with a small particle size reach any one of stages 1 to MOC, but the smaller the particle size, the higher the numbered stage, and the drug particles that have passed through stage 7 are collected by MOC.
  • the amount of active ingredient having an aerodynamic particle size of 4.4 ⁇ m or less is defined as the amount of fine particles (fine particle dose: FPD) out of the amount of active ingredient contained, and breathing is performed using this parameter.
  • FPD fine particle dose
  • Test Example 1 Evaluation of the amount of fine particles when the inavir inhalation powder is dispersed in purified water The amount of fine particles in a liquid in which 400 mg of 20 mg of inavir inhalation powder (containing 80 mg of the active ingredient as an anhydride) is dispersed in 8 ml of purified water Table 12 shows the results of the evaluation. The amount of fine particles (FPD) was only 0.4 mg.
  • Test Example 4 Influence of Dispersant
  • Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) obtained in Examples 4 and 5 were used as dispersants.
  • the amount of fine particles was evaluated for the composition to which was added. The results are shown in Table 15. Even in a system in which both substances were added as a dispersant, a good amount of fine particles was shown.
  • Example 6 Stability evaluation of freeze-dried preparation The stability evaluation of the freeze-dried preparation of Example 7 was performed. The amount of fine particles was evaluated by the same method as in Example 15 to obtain a nebulizer composition. Impurities were evaluated by the HPLC method. The results are shown in Table 17. This drug was confirmed to be stable up to 6 months.
  • Test Example 7 Fine particle amount evaluation of a composition containing an active ingredient having various amounts of tyloxapol and various particle diameters Fine particles obtained by changing the particle diameter of an active ingredient in a composition containing tyloxapol as a dispersant The amount was evaluated. The results are shown in Table 18. A good fine particle amount was shown in the range of the amount of tyloxapol and the particle diameter of the active ingredient in this example.
  • Example 8 The lyophilized preparation obtained in Example 9 was dispersed in purified water as Comparative Example 4, and the composition obtained in Example 17 and the amount of fine particles were compared. The results are shown in Table 19. It was shown that the amount of fine particles was improved by adding sodium chloride as an osmotic pressure regulator.
  • Table 20 shows the particle amount evaluation results of Example 17, Examples 23 to 25, Example 30, and Examples 34 to 35. It has been shown that FPD increases with increasing active ingredient content.
  • Blood was collected before and after inhalation of the active ingredient, and the drug concentration in plasma was measured.
  • the alveolar lavage was performed after administration of the active ingredient by inhalation, and the drug concentrations in alveolar mucus and alveolar macrophages were measured.
  • the drug concentration was measured for active ingredients and active metabolites.
  • a validated liquid chromatography tandem mass spectrometry method was used for drug concentration measurements.
  • the dosage is 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg as the active ingredient (indicating the weight as an anhydride. The same applies in Test Example 10 below).
  • Administered for the dosing, nebulizer compositions prepared according to Example 29, Example 30, Example 31, Example 32, and Example 33 were used. Moreover, the safety
  • the concentration of active metabolite in plasma when a composition containing an active ingredient is administered by single inhalation using a nebulizer for Japanese healthy adult males is the maximum plasma concentration attainment time (Tmax, median) Was 4.0 to 6.0 hours, and the elimination half-life (T 1/2 , average value) was 58.29 to 165.8 hours.
  • the maximum plasma concentration of active metabolite in plasma (Cmax) and the area under plasma concentration after administration (AUClast) increased approximately in proportion to the dose.
  • intra-alveolar lavage is performed using the bronchoalveolar lavage () BAL) method, the alveolar lavage fluid is collected, and the drug concentration in alveolar mucus and alveolar macrophages was measured.
  • the active metabolite concentration in alveolar mucus showed the highest concentration at the time of the first measurement (4 hours after the start of administration).
  • the concentration was 1459 ng / mL, and it was about 4.2 ⁇ M in terms of the molecular weight of the active metabolite (346.34).
  • the concentration after 168 hours from the start of administration was 636.1 ng / mL (about 1.8 ⁇ M).
  • the concentration of active metabolites in alveolar mucus after a single inhalation administration of a nebulizer composition for Japanese healthy adult males is the reported inhaled powder (effective
  • the concentration of the active metabolite in the alveolar mucus after a single inhalation administration of 40 mg of the component is over the IC 50 value over a long period of time after the administration of the active ingredient in both the inhalation powder and the nebulizer composition The concentration was maintained (Antimicrobial Agents and Chemotherapy 2012, vol.56, No.7, p3873-3878).
  • the active metabolite in alveolar mucus when a single dose of 160 mg as an active ingredient is administered to a Japanese healthy adult man using a nebulizer is the type A and B at the first evaluation time point (4 hours after the start of administration) after administration. Concentrations well above the IC 50 value for neuramidase of influenza A virus were observed, and the concentration lasted for a long time, indicating the possibility of developing sustained efficacy.
  • Test Example 11 Comparative test of pharmacokinetics between nebulizer composition and inhalation powder for healthy adult male subjects A composition for nebulizer (active ingredient amount 160 mg, weight as an anhydride is shown) to a Japanese healthy adult male. ), And pharmacokinetics in alveolar mucus after single inhalation administration of inhalable powder (active ingredient amount 40 mg, indicates weight as anhydride).
  • the nebulizer composition the nebulizer composition prepared according to Example 31 was used.
  • the inhalation powder 20 mg of a commercially available inavir inhalation powder was used. The results are shown in Table 21.
  • Cmax, AUCinf, Tmax, and T1 / 2 represent estimated values (standard errors).
  • the maximum plasma concentration (Cmax) showed a higher tendency when administered by inhalation powder, but after the time when the maximum plasma concentration (Cmax) was shown, the nebulizer Composition tends to be higher than inhaled powder, and the area under the plasma concentration-time curve (AUCinf) up to infinity is about 2.8 times higher in the nebulizer composition, with the highest plasma Concentration arrival time (Tmax, median) and disappearance half-life (T1 / 2 , average value) were not different between the nebulizer composition and the inhaled powder.
  • Tmax plasma Concentration arrival time
  • T1 / 2 disappearance half-life
  • inavir powder 20 mg is an inhaler powder containing laninamivir octanoate hydrate as an active ingredient, and an active ingredient amount of 40 mg (anhydrous), which is an approved dose for children over 10 years of age and adults. (Indicating the weight as a product) has been confirmed to be effective in treating and preventing influenza virus infection.
  • the effective amount of the active ingredient of the nebulizer composition may be 80 mg to 320 mg to show an influenza treatment / prevention effect.
  • the dose approved for children under 10 years old is the amount of active ingredient approved for children over 10 years old and adults (indicating the weight as an anhydride) It is confirmed that a therapeutic effect of influenza virus infection is shown at an active ingredient amount of 20 mg (indicating the weight as an anhydride), which is half the amount of).
  • the nebulizer composition active ingredient 160 mg
  • the nebulizer composition can be expected to have a therapeutic / preventive effect on infectious diseases of type A and type B influenza virus inhalation powder (active ingredient 40 mg). Therefore, there is a possibility that the nebulizer composition may be effective at an active ingredient amount of 80 mg, which is a half of an effective dose of 160 mg, which is expected to be effective in children and adults 10 years or older.
  • the nebulizer composition active ingredient 80 to 320 mg
  • the nebulizer composition that can be expected to have a therapeutic / preventive effect for Japanese healthy adult males may also have a therapeutic / preventive effect for the elderly.
  • the active ingredient amount of the nebulizer composition is 160 mg.
  • the effectiveness of the therapeutic use is defined as the time from the onset of influenza, that is, the time from the end of medication to the first point at which all influenza symptoms disappear or become mild, and last for 21.5 hours or longer. To do.
  • Test Example 14 Examination of therapeutic effect on pediatric patient subjects An uncontrolled open-label study is conducted on patients with influenza virus infection younger than 10 years.
  • the amount of the active ingredient in the nebulizer composition is 160 mg.
  • the effectiveness of the therapeutic use is the primary endpoint of the time from influenza onset, i.e., the time from the end of medication to the first time that all influenza symptoms disappear or become mild and continue for 21.5 hours or more. To do.

Abstract

The present invention provides a composition for nebulizers, which is useful for preventing and/or treating influenza virus infection. This composition for nebulizers contains laninamivir octanoate ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient.

Description

ネブライザー用組成物Nebulizer composition
　本発明は、ノイラミニダーゼ阻害活性を有するラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分とする、インフルエンザウイルス感染症の治療又は予防のためのネブライザー用組成物に関する。 The present invention relates to a nebulizer composition for treating or preventing influenza virus infection, comprising as an active ingredient laninamivir octanoate hydrate having neuraminidase inhibitory activity or a pharmacologically acceptable salt thereof.
　ラニナミビルオクタン酸エステル水和物は優れたノイラミニダーゼ阻害作用を示し、受容者の呼吸器へ投与され、受容者の呼吸器組織（上気道、肺等）に滞留させることにより、インフルエンザウイルス感染症の治療／予防効果を発揮する（特許文献１～３）。　 Laninamivir octanoate hydrate exhibits an excellent neuraminidase inhibitory action and is administered to the recipient's respiratory tract, causing it to stay in the recipient's respiratory tissues (upper respiratory tract, lungs, etc.), causing influenza virus infection (Patent Documents 1 to 3). *
　ラニナミビルオクタン酸エステル水和物は、受容者の呼吸器組織に滞留させることにより、抗インフルエンザ作用を示すため、ラニナミビルオクタン酸エステル水和物を非経口経路で呼吸器組織へ到達させる投与法および投与剤形が必要である。そこで、ラニナミビルオクタン酸エステル水和物を非経口経路で投与する剤形として、乾燥粉末吸入製剤が開示されている（特許文献４）。 Because laninamivir octanoate hydrate exhibits anti-influenza action by retention in the recipient's respiratory tissue, it causes parenteral route to reach the respiratory tissue by parenteral route There is a need for administration methods and dosage forms. Therefore, a dry powder inhalation preparation has been disclosed as a dosage form for administering laninamivir octanoate hydrate by the parenteral route (Patent Document 4).
　乾燥粉末吸入製剤は、具体的には、吸入用の粉末処方が、カプセル、ブリスター、デバイス内のリザーバーやドージングディスク等の容器に格納され、１回分の投与量の粉末を受容者自身の吸気によってデバイスから吸入する。しかし、小児や高齢者、呼吸機能が低下した患者などの自発呼吸困難者は、乾燥粉末吸入製剤を適切に扱えず、十分な量の薬物を吸入することが困難な場合がある。また、自発呼吸困難者は、十分な量の吸気を確保しづらい場合もある。このような自発呼吸困難者にとって、十分量の薬物を安定して呼吸器組織へ到達させるために好適な投与法および投与剤形の開発が望まれる。 Specifically, a dry powder inhalation preparation is prepared by storing a powder formulation for inhalation in a container such as a capsule, a blister, a reservoir in a device, a dosing disk, or the like. Inhale from device. However, those with difficulty in spontaneous breathing, such as children, the elderly, and patients with reduced respiratory function, may not be able to properly handle dry powder inhalation preparations and may be difficult to inhale a sufficient amount of drug. In addition, a person with difficulty in spontaneous breathing may have difficulty in securing a sufficient amount of inspiration. For such a person with difficulty in spontaneous breathing, it is desired to develop a suitable administration method and dosage form so that a sufficient amount of drug can stably reach the respiratory tissue.
　耳鼻咽喉科領域では、小児でも確実に吸入できる投与法として、ネブライザーによる投与法が知られている。また、気管支喘息や嚢胞性線維症などの呼吸器疾患の治療においても、小児や自発呼吸困難者でも確実に吸入できる投与法として、ネブライザーによる投与が行われている。このように、ネブライザーは広く小児、高齢者や自発呼吸困難者を含む患者に用いられてきているにも関わらず、インフルエンザウイルス感染症のためのネブライザー用の組成物は、これまで上市されていない。 In the field of otolaryngology, an administration method using a nebulizer is known as an administration method that can be surely inhaled by children. Further, in the treatment of respiratory diseases such as bronchial asthma and cystic fibrosis, administration by a nebulizer is performed as an administration method that can be surely inhaled by children and those with difficulty in spontaneous breathing. Thus, although nebulizers have been widely used in patients, including children, the elderly, and those with difficulty breathing, no nebulizer composition for influenza virus infection has ever been launched. .
　抗インフルエンザ薬、とりわけノイラミニダーゼ阻害剤として、オセルタミビルリン酸塩（商標名タミフル、特許文献５）、ザナミビル水和物（商標名リレンザ、特許文献６）及びペラミビル水和物（商標名ラピアクタ、特許文献７）が市販されている。　 As anti-influenza drugs, especially neuraminidase inhibitors, oseltamivir phosphate (trade name Tamiflu, Patent Document 5), zanamivir hydrate (trade name Relenza, Patent Document 6) and peramivir hydrate (trade name Rapiacta, Patent Document 7) ) Is commercially available. *
　タミフルは、経口投与製剤であり、カプセル剤あるいはドライシロップ製剤として市販されている。また、ラピアクタは点滴静注用の注射剤である。これらの薬剤は、投与経路が吸入でないため、投与手段としてネブライザーの選択は不可能である。 Tamiflu is a preparation for oral administration and is commercially available as a capsule or dry syrup preparation. Lapiactor is an injection for intravenous infusion. Since these drugs are not administered by inhalation, it is impossible to select a nebulizer as an administration means.
　ザナミビル（商標名リレンザ）は、吸入用製剤であるが、複数日間、連続投与が必要である。ネブライザーを所有していない大部分の患者にとって、リレンザをネブライザーで投与するのは、投与の度に通院を要するため体への負担がある。 Zanamivir (trade name Relenza) is a formulation for inhalation, but requires continuous administration for multiple days. For most patients who do not have a nebulizer, administering Relenza with a nebulizer is burdensome to the body because it requires a visit to each dose.
　なるべく少ない投与回数で治療が完結するような、ノミラミニダーゼ阻害剤のネブライザー用製剤の開発が望まれる。 Development of a nebulizer preparation for a nomiraminidase inhibitor that can be completed with as few administrations as possible is desired.
特許第３２０９９４６号公報（米国特許第６３４０７０２号明細書、欧州特許第８２３４２８号明細書）Japanese Patent No. 3209946 (U.S. Pat. No. 6,340,702, European Patent No. 823428) 特許第３９２００４１号公報（米国特許第６８４４３６３号明細書、欧州特許第１２７７７５０号明細書）Japanese Patent No. 3920041 (U.S. Pat. No. 6,844,363, European Patent No. 1,277,750) 特許第４２０５３１４号公報（国際公開第２００１／０８０８９２号パンフレットJapanese Patent No. 4205314 (International Publication No. 2001/080892 pamphlet) 特許第５６９７１９９号公報（国際公開第２０１０／０７４１１３号パンフレット）Japanese Patent No. 5697199 (Pamphlet of International Publication No. 2010/074113) 国際公開第９６／２６９３３号パンフレットInternational Publication No. 96/26933 Pamphlet 国際公開第９１／１６３２０号パンフレットWO91 / 16320 pamphlet 特許第４１０２０２２号公報（米国特許第６５０３７４５号明細書、欧州特許第１０４００９４号明細書）Japanese Patent No. 4102022 (US Pat. No. 6,503,745, European Patent No. 1040094)
　本発明者らは、インフルエンザウイルス感染症を治療／予防する薬剤について長年にわたり鋭意検討を行った。その結果、ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分とし、組成の適切な選択、粒子径の適切な調節により受容者の呼吸器組織（上気道、肺等）に効率よく到達させることができ（すなわち、呼吸器到達性に優れる）、さらに、吸入時の刺激性が低く、物理的安定性にも優れた、ネブライザー用の吸入液剤とすることができることを見出し、本発明を完成した。 The present inventors have intensively studied for many years on drugs for treating / preventing influenza virus infection. As a result, laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is used as an active ingredient, and the recipient's respiratory tissues (upper respiratory tract, lungs, etc.) are selected by appropriate selection of the composition and appropriate adjustment of the particle size. ) (E.g., excellent respiratory reachability), low irritation at the time of inhalation, and excellent physical stability. The headline and the present invention were completed.
　本発明は、
［１］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、さらに分散剤と浸透圧調節剤を含有するネブライザー用組成物、
［２］　ラニナミビルオクタン酸エステル水和物を１～２０重量％含有する前記［１］に記載のネブライザー用組成物、
［３］　ラニナミビルオクタン酸エステル水和物を３～１０重量％含有する前記［１］又は［２］に記載のネブライザー用組成物、
［４］　ラニナミビルオクタン酸エステル水和物のレーザー回折散乱式粒度分布測定法における５０重量％の粒子径が５．０μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が１２．０μｍ以下である前記［１］乃至［３］のいずれか１項に記載のネブライザー用組成物、
［５］　ラニナミビルオクタン酸エステル水和物のレーザー回折散乱式粒度分布測定法における５０重量％の粒子径が３．２μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が８．０μｍ以下である前記［１］乃至［３］のいずれか１項に記載のネブライザー用組成物、
［６］　分散剤が、ポリソルベート、ソルビタンモノラウレート、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）及び、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）からなる群より選択される１種若しくは２種を組み合わせたものである、前記［１］乃至［５］のいずれか１項に記載のネブライザー用組成物、
［７］　分散剤がチロキサポールである、前記［１］乃至［５］のいずれか１項に記載のネブライザー用組成物、
［８］　チロキサポールの含有率が、０．０１～１重量％である、前記［７］に記載のネブライザー用組成物、
［９］　チロキサポールの含有率が、０．０５～０．５重量％である、前記［７］に記載のネブライザー用組成物、
［１０］　分散剤がポリオキシエチレンソルビタンモノラウレート及びソルビタンモノラウレートである、前記［１］乃至［５］のいずれか１項に記載のネブライザー用組成物、
［１１］　ポリオキシエチレンソルビタンモノラウレートの含有率が０．０１～０．５重量％であり、ソルビタンモノラウレートの含有率が０．０１～０．５重量％である前記［１０］に記載のネブライザー用組成物、
［１２］　ポリオキシエチレンソルビタンモノラウレートの含有率が０．０３８～０．２重量％であり、ソルビタンモノラウレートの含有率が０．１～０．２重量％である前記［１２］に記載のネブライザー用組成物、
［１３］　浸透圧調節剤が塩化ナトリウム又は乳糖水和物である、前記［１］乃至［１２］のいずれか１項に記載のネブライザー用組成物、
［１４］　浸透圧調節剤が塩化ナトリウムである、前記［１］乃至［１２］のいずれか１項に記載のネブライザー用組成物、
［１５］　塩化ナトリウムの含有率が０．４５～１．８重量％である前記［１３］又は［１４］のいずれか１項に記載のネブライザー用組成物、
［１６］　乳糖水和物の含有率が５～１０重量％である前記［１３］に記載のネブライザー用組成物、
［１７］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、さらに分散剤を含有する凍結乾燥製剤、
［１８］　分散剤が、ポリソルベート、ソルビタンモノラウレート、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、及び、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）からなる群から選択される１種若しくは２種を組み合わせたものである、前記［１７］に記載の凍結乾燥製剤、
［１９］　分散剤がチロキサポールである前記［１７］に記載の凍結乾燥製剤、
［２０］　さらに浸透圧調節剤を含有する前記［１７］乃至［１９］のいずれか１項に記載の凍結乾燥製剤、
［２１］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩の含有率が５５～９５重量％であり、分散剤の含有率が１～１０重量％であり、浸透圧調節剤の含有率が４～３５重量％である前記［２０］に記載の凍結乾燥製剤、
［２２］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩とチロキサポールからなる凍結乾燥製剤、
［２３］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩の含有率が９３．０～９８．５重量％であり、チロキサポールの含有率が１．５～７．０重量％である前記［２２］に記載の凍結乾燥製剤。
［２４］　前記［１］乃至［１６］のいずれか１項に記載のネブライザー用組成物を、ネブライザーを用いて噴霧して吸入する方法
［２５］　前記［１７］乃至［２３］のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、ネブライザーを用いて噴霧して吸入する方法、
［２６］　前記［１］乃至［１６］のいずれか１項に記載のネブライザー用組成物からなるインフルエンザウイルス感染症の予防又は治療剤、
［２７］　前記［１７］乃至［２３］のいずれか１項に記載の凍結乾燥製剤を懸濁用液にて分散して調製される吸入液剤からなるインフルエンザウイルス感染症の予防又は治療剤、
［２８］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して４０乃至３２０ｍｇである、前記［１］乃至［１６］のいずれか１項に記載のネブライザー用組成物、
［２９］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して８０ｍｇである、前記［１］乃至［１６］のいずれか１項に記載のネブライザー用組成物、
［３０］　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して１６０ｍｇである、前記［１］乃至［１６］のいずれか１項に記載のネブライザー用組成物、
［３１］　前記［１］乃至［１６］、及び、前記［２８］乃至［３０］のいずれか１項に記載のネブライザー用組成物を、インフルエンザウイルスの発症前のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の予防方法。
［３２］　前記［１］乃至［１６］、及び、前記［２８］乃至［３０］のいずれか１項に記載のネブライザー用組成物を、インフルエンザウイルスの発症時のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザ感染症の治療方法、
［３３］　前記［１７］乃至［２３］のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、インフルエンザウイルスの発症前のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の予防方法、
及び、
［３４］　前記［１７］乃至［２３］のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、インフルエンザウイルスの発症時のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の治療方法
である。 The present invention
[1] A composition for nebulizers containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersant and an osmotic pressure regulator,
[2] The nebulizer composition according to [1] above, containing 1 to 20% by weight of laninamivir octanoate hydrate,
[3] The nebulizer composition according to the above [1] or [2], containing 3 to 10% by weight of laninamivir octanoate hydrate,
[4] The particle size of 50% by weight in the laser diffraction / scattering particle size distribution measurement method of laninamivir octanoate hydrate is 5.0 μm or less and 90% by weight in the laser diffraction / scattering particle size distribution measurement method The composition for a nebulizer according to any one of the above [1] to [3], wherein the particle diameter of
[5] The particle size of 50% by weight in the laser diffraction / scattering particle size distribution measurement method of laninamivir octanoate hydrate is 3.2 μm or less and 90% by weight in the laser diffraction / scattering particle size distribution measurement method The composition for a nebulizer according to any one of the above [1] to [3], wherein the particle diameter of is [1] to [3],
[6] The dispersant is a combination of one or two selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa), [1] to [5] the composition for a nebulizer according to any one of
[7] The composition for a nebulizer according to any one of [1] to [5], wherein the dispersant is tyloxapol,
[8] The nebulizer composition according to [7], wherein the content of tyloxapol is 0.01 to 1% by weight,
[9] The nebulizer composition according to [7], wherein the content of tyloxapol is 0.05 to 0.5% by weight,
[10] The nebulizer composition according to any one of [1] to [5], wherein the dispersant is polyoxyethylene sorbitan monolaurate and sorbitan monolaurate,
[11] In the above [10], the content of polyoxyethylene sorbitan monolaurate is 0.01 to 0.5% by weight, and the content of sorbitan monolaurate is 0.01 to 0.5% by weight. The composition for nebulizers as described,
[12] In the above [12], the content of polyoxyethylene sorbitan monolaurate is 0.038 to 0.2% by weight, and the content of sorbitan monolaurate is 0.1 to 0.2% by weight. The composition for nebulizers as described,
[13] The nebulizer composition according to any one of [1] to [12], wherein the osmotic pressure regulator is sodium chloride or lactose hydrate.
[14] The nebulizer composition according to any one of [1] to [12], wherein the osmotic pressure regulator is sodium chloride,
[15] The nebulizer composition according to any one of [13] or [14], wherein the sodium chloride content is 0.45 to 1.8% by weight,
[16] The composition for a nebulizer according to the above [13], wherein the lactose hydrate content is 5 to 10% by weight,
[17] A freeze-dried preparation containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersant,
[18] The dispersant is a combination of one or two selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). The freeze-dried preparation according to the above [17],
[19] The lyophilized preparation according to the above [17], wherein the dispersant is tyloxapol,
[20] The freeze-dried preparation according to any one of [17] to [19], further containing an osmotic pressure regulator,
[21] An osmotic pressure regulator wherein the content of laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is 55 to 95% by weight, and the content of the dispersant is 1 to 10% by weight. The lyophilized preparation according to the above [20], wherein the content of is 4 to 35% by weight,
[22] A freeze-dried preparation comprising laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof and tyloxapol,
[23] The content of laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is 93.0 to 98.5% by weight, and the content of tyloxapol is 1.5 to 7.0% by weight. The lyophilized preparation according to the above [22].
[24] A method of spraying and inhaling the nebulizer composition according to any one of [1] to [16] using a nebulizer [25] any one of [17] to [23] The lyophilized preparation according to the item, dispersed in a suspension liquid to make an inhalation solution, and sprayed using a nebulizer for inhalation,
[26] A preventive or therapeutic agent for influenza virus infection comprising the nebulizer composition according to any one of [1] to [16],
[27] A preventive or therapeutic agent for influenza virus infection comprising an inhalation solution prepared by dispersing the lyophilized preparation according to any one of [17] to [23] in a suspension liquid,
[28] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 40 to 320 mg in terms of anhydride per administration. The nebulizer composition according to any one of the above [1] to [16],
[29] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 80 mg in terms of anhydride per administration, The nebulizer composition according to any one of [1] to [16],
[30] It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 160 mg in terms of anhydride per administration, The nebulizer composition according to any one of [1] to [16],
[31] The nebulizer composition according to any one of [1] to [16] and [28] to [30] is applied to a human respiratory organ before the onset of influenza virus. A method for preventing influenza virus infection by spraying and inhaling.
[32] The nebulizer composition according to any one of [1] to [16] and [28] to [30] is applied to a human respiratory organ at the onset of influenza virus. A method of treating influenza infection by spraying and inhaling using,
[33] The lyophilized preparation according to any one of [17] to [23] is dispersed in a suspension liquid to form an inhalation solution, and the nebulizer is used in a human respiratory tract before the onset of influenza virus. How to prevent influenza virus infection by spraying and inhaling with
as well as,
[34] The lyophilized preparation according to any one of [17] to [23] is dispersed in a suspension liquid to form an inhalation solution, and the nebulizer is used in a human respiratory tract when influenza virus develops. This is a method for treating influenza virus infection by nebulizing and inhaling.
　本発明のネブライザー用組成物の有効成分はラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩である。ラニナミビルオクタン酸エステル水和物は、下記式（Ｉ）と（ＩＩ）： The active ingredient of the nebulizer composition of the present invention is laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof. Laninamivir octanoate hydrate has the following formulas (I) and (II):
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
で示される、
（Ｉ）：（２Ｒ，３Ｒ，４Ｓ）－３－アセトアミド－４－グアニジノ－２－［（１Ｒ，２Ｒ）－２－ヒドロキシ－1－メトキシ－３－（オクタノイルオキシ）プロピル］－３，４－ジヒドロ－２Ｈ－ピラン－６－カルボン酸　一水和物と、
（ＩＩ）：（２Ｒ，３Ｒ，４Ｓ）－３－アセトアミド－４－グアニジノ－２－［（１Ｓ，２Ｒ）－３－ヒドロキシ－１－メトキシ－２－（オクタノイルオキシ）プロピル］－３，４－ジヒドロ－２Ｈ－ピラン－６－カルボン酸　一水和物の混合物である。 Indicated by
(I): (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1R, 2R) -2-hydroxy-1-methoxy-3- (octanoyloxy) propyl] -3,4 -Dihydro-2H-pyran-6-carboxylic acid monohydrate;
(II): (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1S, 2R) -3-hydroxy-1-methoxy-2- (octanoyloxy) propyl] -3,4 -Dihydro-2H-pyran-6-carboxylic acid monohydrate mixture.
　上記式（Ｉ）および（ＩＩ）で示されるラニナミビルオクタン酸エステル水和物は、分子内にグアニジノ基及びカルボキシル基を有するので、薬理的に毒性を示さない酸又は塩基と結合して薬理上許容される塩を形成することができる。ラニナミビルオクタン酸エステル水和物の「その薬理上許容される塩」とは、このような塩をいう。 Since the laninamivir octanoic acid ester hydrate represented by the above formulas (I) and (II) has a guanidino group and a carboxyl group in the molecule, it binds to a pharmacologically non-toxic acid or base. A top acceptable salt can be formed. The “pharmacologically acceptable salt” of laninamivir octanoate ester hydrate refers to such a salt.
　「薬理上許容される塩」としては、例えばフッ化水素酸塩、塩化水素酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩；硝酸塩、過塩素酸塩、硫酸塩、リン酸塩のような無機酸塩；メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩のようなアルカンスルホン酸塩；ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリールスルホン酸塩；酢酸塩、トリフルオロ酢酸塩、クエン酸塩、酒石酸塩、しゅう酸塩、マレイン酸塩のような有機酸塩；グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩；リチウム塩、ナトリウム塩、カリウム塩のようなアルカリ金属塩；カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩；アルミニウム塩、鉄塩、亜鉛塩、銅塩、ニッケル塩、コバルト塩のような金属塩；アンモニウム塩、ｔ－オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、エチレンジアミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、プロカイン塩、エタノールアミン塩、ジエタノールアミン塩、ピペラジン塩、テトラメチルアンモニウム塩のような有機アミン若しくは有機アンモニウム塩等を挙げることができ、好適にはリチウム塩、ナトリウム塩、カリウム塩のようなアルカリ金属塩；酢酸塩、トリフルオロ酢酸塩のような有機酸塩；または塩酸塩、硫酸塩のような無機酸塩である。 Examples of the “pharmacologically acceptable salt” include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, Inorganic acid salts such as sulfate and phosphate; Alkane sulfonate such as methane sulfonate, ethane sulfonate and trifluoromethane sulfonate; benzene sulfonate and p-toluene sulfonate Aryl sulfonates; organic acid salts such as acetate, trifluoroacetate, citrate, tartrate, oxalate, maleate; glycine, lysine, arginine, ornithine, glutamate, asparagine Amino acid salts such as acid salts; alkali metal salts such as lithium salts, sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Metal salts such as luminium salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt; ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, ethylenediamine salt, guanidine salt, diethylamine Salt, triethylamine salt, dicyclohexylamine salt, procaine salt, ethanolamine salt, diethanolamine salt, piperazine salt, organic amine salt such as tetramethylammonium salt, and the like, preferably lithium salt, sodium salt Alkali metal salts such as potassium salts; organic acid salts such as acetates and trifluoroacetates; or inorganic acid salts such as hydrochlorides and sulfates.
　ラニナミビルオクタン酸エステル水和物及びその薬理上許容される塩は、大気中に放置したり、水と混和したりすることによって水を吸収し、水和物を形成する場合がある。ラニナミビルオクタン酸エステル水和物やその薬理上許容される塩の水和物とは、このような水和物をいう。 The laninamivir octanoic acid ester hydrate and its pharmacologically acceptable salt may absorb water by being left in the atmosphere or mixed with water to form a hydrate. The hydrate of laninamivir octanoate ester or a pharmacologically acceptable salt thereof refers to such a hydrate.
　ラニナミビルオクタン酸エステル水和物及びその薬理上許容される塩は、分子内に不斉炭素を有し、立体異性体（エナンチオマーおよびジアステレオマーを含む）が存在する。これらの立体異性体およびそれらの任意の割合の混合物（ラセミ体を含む）は、本発明の有効成分であるラニナミビルオクタン酸エステル水和物及びその薬理上許容される塩に包含される。 Laninamivir octanoic acid ester hydrate and pharmacologically acceptable salts thereof have an asymmetric carbon in the molecule and have stereoisomers (including enantiomers and diastereomers). These stereoisomers and mixtures in arbitrary proportions (including racemates) are included in the laninamivir octanoic acid ester hydrate and pharmacologically acceptable salts thereof which are the active ingredients of the present invention.
　上記式（Ｉ）で表される（２Ｒ，３Ｒ，４Ｓ）－３－アセトアミド－４－グアニジノ－２－［（１Ｒ，２Ｒ）－２－ヒドロキシ－1－メトキシ－３－（オクタノイルオキシ）プロピル］－３，４－ジヒドロ－２Ｈ－ピラン－６－カルボン酸　一水和物は、温血動物に投与されたとき、側鎖の３位のアシルオキシ基が加水分解等の代謝反応によりヒドロキシル基に変換され、生成した化合物（ＩＩＩ）： (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1R, 2R) -2-hydroxy-1-methoxy-3- (octanoyloxy) propyl represented by the above formula (I) ] 3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate, when administered to warm-blooded animals, the acyloxy group at the 3-position of the side chain is converted to a hydroxyl group by metabolic reaction such as hydrolysis. Compound (III) converted and produced:
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
が薬理活性を示すことが知られている（特許文献１等）。また、上記式（ＩＩ）で表される（２Ｒ，３Ｒ，４Ｓ）－３－アセトアミド－４－グアニジノ－２－［（１Ｓ，２Ｒ）－３－ヒドロキシ－１－メトキシ－２－（オクタノイルオキシ）プロピル］－３，４－ジヒドロ－２Ｈ－ピラン－６－カルボン酸　一水和物が温血動物に投与されたとき、側鎖の2位のアシルオキシ基が加水分解等の代謝反応によりヒドロキシル基に変換され、同様に化合物（ＩＩＩ）が生成する。温血動物の生体内では、化合物（Ｉ）および化合物（ＩＩ）はいずれも活性代謝物である同一の化合物（ＩＩＩ）へ変換される。 Is known to exhibit pharmacological activity (Patent Document 1, etc.). In addition, (2R, 3R, 4S) -3-acetamido-4-guanidino-2-[(1S, 2R) -3-hydroxy-1-methoxy-2- (octanoyloxy) represented by the above formula (II) ) Propyl] -3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate is administered to a warm-blooded animal, the acyloxy group at the 2-position of the side chain is converted into a hydroxyl group by metabolic reaction such as hydrolysis. In the same manner to produce compound (III). In the warm-blooded animal, both compound (I) and compound (II) are converted to the same compound (III) which is an active metabolite.
　本発明のネブライザー用組成物に含有されるラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩の粒子径は、好ましくは、レーザー回折散乱式粒度分布測定法における５０重量％の粒子径が５．０μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が１２．０μｍ以下であり、より好ましくは、レーザー回折散乱式粒度分布測定法における５０重量％の粒子径が３．２μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が８．０μｍ以下である。 The particle size of laninamivir octanoic acid ester hydrate or pharmacologically acceptable salt thereof contained in the nebulizer composition of the present invention is preferably 50% by weight of particles in the laser diffraction scattering type particle size distribution measurement method. The diameter is 5.0 μm or less and the 90% by weight particle size in the laser diffraction / scattering particle size distribution measurement method is 12.0 μm or less, more preferably 50% by weight in the laser diffraction / scattering particle size distribution measurement method. Has a particle size of 3.2 μm or less, and a 90% by weight particle size in the laser diffraction / scattering particle size distribution measurement method is 8.0 μm or less.
　この範囲であると、本発明の有効成分は特に吸入性に優れ、高い呼吸器到達性を有し咽頭を通過して肺深部にまで到達することができ、その結果、高くかつ長期にわたる抗インフルエンザ活性を発揮する。 Within this range, the active ingredient of the present invention is particularly excellent in inhalability, has high respiratory reachability and can pass through the pharynx to reach the deep lung, resulting in high and long-lasting anti-influenza Demonstrate activity.
　本発明のネブライザー用組成物は、上記有効成分に加え、さらに、分散剤と浸透圧調節剤とを含有するネブライザー用の吸入液剤である。 The nebulizer composition of the present invention is an inhalation solution for nebulizers that further contains a dispersant and an osmotic pressure regulator in addition to the above active ingredients.
　本発明において、分散剤とは、ネブライザー用組成物中において、含有される化合物、特に有効成分を液中に均一に分散させるために添加される化合物である。分散剤としては、界面活性剤、あるいは乳化剤を用いることができる。 In the present invention, the dispersant is a compound added to disperse a compound contained in the nebulizer composition, particularly an active ingredient, uniformly in the liquid. As the dispersant, a surfactant or an emulsifier can be used.
　分散剤として、より具体的には、例えば、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）、ポリオキシエチレンソルビタンモノステアレート（ツイーン６０）、ポリオキシエチレンソルビタントリステアレート（ツイーン６５）、又は、ポリオキシエチレンソルビタンモノオレエート（ツイーン８０）のポリソルベート、ソルビタンモノラウレート（スパン２０）、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、及び、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）からなる群より選択される１種若しくは２種を組み合わせたものが例示できる。 More specifically, as the dispersant, for example, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan tristearate (Tween 65), or One selected from the group consisting of polysorbate of polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (span 20), tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa) or What combined 2 types can be illustrated.
　これらの中でも、好ましいのは、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）、ソルビタンモノラウレート（スパン２０）、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）である。ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）とソルビタンモノラウレート（スパン２０）は組み合わせて用いることもできる。 Among these, polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (span 20), tyloxapol, and hydroxypropylmethylcellulose (HPMC) are preferable. Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) can be used in combination.
　これらの中でも、より好ましいのは、チロキサポールであり、あるいは、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）とソルビタンモノラウレート（スパン２０）の２種を組み合わせたものである。 Of these, tyloxapol is more preferable, or a combination of two types of polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20).
　これらの中でも、さらに好ましいのは、チロキサポールである。 Among these, tyloxapol is more preferable.
　本発明のネブライザー用組成物は、浸透圧調節剤を含有する。 The nebulizer composition of the present invention contains an osmotic pressure regulator.
　本発明において、浸透圧調節剤とは、本発明のネブライザー用組成物の浸透圧を調節するために添加される化合物であり、浸透圧調節剤として用いる化合物を選択することによって、本発明のネブライザー用組成物の浸透圧を、体液、具体的には、口腔内や呼吸器組織（上気道、肺等）の体液の浸透圧と等しくすることができる。本発明のネブライザー用組成物を体液と等張とすることによって、本発明のネブライザー用組成物の吸入時の刺激を低くすることができ、かつ、呼吸器組織に到達しうる本発明の有効成分量（微粒子量、ＦＰＤ）を増加させることができる。 In the present invention, the osmotic pressure adjusting agent is a compound added to adjust the osmotic pressure of the nebulizer composition of the present invention. By selecting a compound to be used as the osmotic pressure adjusting agent, the nebulizer of the present invention is selected. The osmotic pressure of the composition for use can be made equal to the osmotic pressure of bodily fluids, specifically bodily fluids in the oral cavity and respiratory tissues (upper respiratory tract, lungs, etc.). By making the nebulizer composition of the present invention isotonic with body fluids, the irritation at the time of inhalation of the nebulizer composition of the present invention can be reduced, and the active ingredient of the present invention that can reach the respiratory tissue The amount (fine particle amount, FPD) can be increased.
　浸透圧調節剤としては、塩化ナトリウム又は乳糖水和物が挙げられる。 Examples of the osmotic pressure regulator include sodium chloride or lactose hydrate.
　これらの中でも、塩化ナトリウムが好ましい。塩化ナトリウムの水溶液として生理食塩水を用いることができる。 Of these, sodium chloride is preferred. Saline can be used as an aqueous solution of sodium chloride.
　ネブライザーで吸入する際の１回あたりの本発明のネブライザー用組成物の容量は、好ましくは、２～８ｍｌ、特に好ましくは、２ｍｌである。 The volume of the nebulizer composition of the present invention per inhalation with a nebulizer is preferably 2 to 8 ml, particularly preferably 2 ml.
　本発明のネブライザー用組成物において、有効成分の含有率は、好ましくは、１～２０重量％であり、より好ましくは、３～１０重量％である。この範囲であると、本発明のネブライザー用組成物を吸入した受容者の呼吸器組織（上気道、肺等）に、十分量の有効成分を供給することができる。 In the nebulizer composition of the present invention, the content of the active ingredient is preferably 1 to 20% by weight, more preferably 3 to 10% by weight. Within this range, a sufficient amount of the active ingredient can be supplied to the respiratory tissues (upper respiratory tract, lungs, etc.) of the recipient who has inhaled the nebulizer composition of the present invention.
　本発明のネブライザー用組成物において、分散剤の含有率は、用いられる化合物により異なり、例えば、チロキサポールを用いる場合は、含有率は、好ましくは、０．０１～１重量％であり、より好ましくは、０．０５～０．５重量％である。 In the nebulizer composition of the present invention, the content of the dispersant varies depending on the compound used. For example, when tyloxapol is used, the content is preferably 0.01 to 1% by weight, more preferably. 0.05 to 0.5% by weight.
　分散剤として、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）を用いる場合は、含有率は、好ましくは、０．１～１重量％である。 When hydroxypropylmethylcellulose (HPMC) is used as a dispersant, the content is preferably 0.1 to 1% by weight.
　分散剤として、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）を用いる場合は、含有率は、０．１～０．５重量％、好ましくは０．１３８～０．４重量％である。 When polyoxyethylene sorbitan monolaurate (Tween 20) is used as a dispersant, the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
　分散剤として、ソルビタンモノラウレート（スパン２０）を用いる場合は、含有率は、０．１～０．５重量％、好ましくは０．１３８～０．４重量％である。 When sorbitan monolaurate (span 20) is used as the dispersant, the content is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
　分散剤として、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）とソルビタンモノラウレート（スパン２０）を併せて用いても良い。ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）とソルビタンモノラウレート（スパン２０）を併せて用いる場合は、含有率は、好ましくは、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）が０．０３８～０．２重量％、ソルビタンモノラウレート（スパン２０）が０．１～０．２重量％である。 As the dispersant, polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) may be used in combination. When polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) are used in combination, the content is preferably from 0.038 to polyoxyethylene sorbitan monolaurate (Tween 20). 0.2 wt% and sorbitan monolaurate (span 20) is 0.1 to 0.2 wt%.
　この範囲であると、本発明のネブライザー用組成物中において有効成分が優れた分散性を示すからである。 This is because, within this range, the active ingredient exhibits excellent dispersibility in the nebulizer composition of the present invention.
　本発明のネブライザー用組成物において、浸透圧調節剤の含有率は、用いられる化合物により異なる。例えば、浸透圧調節剤として塩化ナトリウムを用いる場合は、本発明のネブライザー組成物中、塩化ナトリウムは、好ましくは、０．４５～１．８重量％であり、乳糖水和物を用いる場合は、乳糖水和物は、好ましくは、５～１０重量％である。 In the nebulizer composition of the present invention, the content of the osmotic pressure regulator varies depending on the compound used. For example, when sodium chloride is used as the osmotic pressure regulator, sodium chloride is preferably 0.45 to 1.8% by weight in the nebulizer composition of the present invention, and when lactose hydrate is used, Lactose hydrate is preferably 5 to 10% by weight.
　本発明の凍結乾燥製剤は、ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、さらに分散剤、あるいはさらに浸透圧調節剤を含有する。本発明の凍結乾燥製剤を懸濁用液で分散することにより、本発明のネブライザー用組成物が得られる。 The freeze-dried preparation of the present invention contains laninamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further contains a dispersant or further an osmotic pressure regulator. The nebulizer composition of the present invention is obtained by dispersing the lyophilized preparation of the present invention with a suspension liquid.
　本発明の凍結乾燥製剤に含有される分散剤は、本発明のネブライザー用組成物に含有される分散剤と同じものである。 The dispersant contained in the freeze-dried preparation of the present invention is the same as the dispersant contained in the nebulizer composition of the present invention.
　本発明の凍結乾燥製剤に含有されうる浸透圧調節剤も、本発明のネブライザー用組成物に含有される浸透圧調節剤と同じものである。 The osmotic pressure regulator that can be contained in the freeze-dried preparation of the present invention is also the same as the osmotic pressure regulator contained in the nebulizer composition of the present invention.
　本発明の凍結乾燥製剤が、有効成分、分散剤、及び、浸透圧調節剤を含む場合、凍結乾燥製剤に含有される有効成分の含有率は、５５～９５重量％であり、分散剤の含有率は、１．０～１０．０重量％であり、浸透圧調節剤の含有率は、４～３５重量％である。 When the freeze-dried preparation of the present invention contains an active ingredient, a dispersant, and an osmotic pressure regulator, the content of the active ingredient contained in the freeze-dried preparation is 55 to 95% by weight, and the inclusion of the dispersant The rate is 1.0 to 10.0% by weight, and the content of the osmotic pressure regulator is 4 to 35% by weight.
　本発明の凍結乾燥製剤では、分散剤として２種を併用することもできる。例えば、分散剤として、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）及びソルビタンモノラウレート（スパン２０）を併用し、浸透圧調節剤として塩化ナトリウムを用いる場合は、凍結乾燥製剤に含有される有効成分の含有率は６０～９０重量％であり、ポリオキシエチレンソルビタンモノラウレート（ツイーン２０）の含有率は０．５～５．０重量％であり、ソルビタンモノラウレート（スパン２０）の含有率は１．５～５．０重量％であり、塩化ナトリウムの含有率は８．０～３０重量％であるのが好ましい。 In the lyophilized preparation of the present invention, two kinds of dispersants can be used in combination. For example, when polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) are used in combination as a dispersant and sodium chloride is used as the osmotic pressure regulator, the effective content contained in the lyophilized formulation The content of the component is 60 to 90% by weight, the content of polyoxyethylene sorbitan monolaurate (Tween 20) is 0.5 to 5.0% by weight, and the content of sorbitan monolaurate (span 20) The ratio is 1.5 to 5.0% by weight, and the content of sodium chloride is preferably 8.0 to 30% by weight.
　本発明の凍結乾燥製剤は、有効成分と、分散剤であるチロキサポールのみを含むものであってもよい。このような凍結乾燥製剤では、凍結乾燥製剤に含有される有効成分の含有率は、９３．０～９８．５重量％であり、分散剤の含有率は１．５～７．０重量％である。 The lyophilized preparation of the present invention may contain only an active ingredient and a tyloxapol as a dispersant. In such a freeze-dried preparation, the content of the active ingredient contained in the freeze-dried preparation is 93.0 to 98.5% by weight, and the content of the dispersant is 1.5 to 7.0% by weight. is there.
　本発明の凍結乾燥製剤より調製される本発明のネブライザー用組成物は、ネブライザー、好ましくはジェット式ネブライザー（コンプレッサー式ネブライザーとも呼ばれる）を用いて、受容者に投与される。 The nebulizer composition of the present invention prepared from the freeze-dried preparation of the present invention is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
　本発明のネブライザー用組成物は、組成物中での有効成分の分散性が優れているため、小児や高齢者、呼吸機能が低下した人といった自発呼吸が困難な受容者であっても、受容者の呼吸器組織（上気道、肺等）に有効成分が効率よく到達することができる。　　 The nebulizer composition of the present invention has excellent dispersibility of the active ingredient in the composition, so even if it is a recipient who is difficult to breathe spontaneously, such as children, elderly people, and those with reduced respiratory function. The active ingredient can efficiently reach the respiratory tissues (upper airways, lungs, etc.) of the person. *
　有効成分が特定の粒子径分布を有する本発明のネブライザー用組成物では、有効成分が、受容者の呼吸器組織、特に上気道や肺にまで到達することができ、従って、高くかつ長期にわたる抗インフルエンザ活性が維持される。 In the nebulizer composition of the present invention in which the active ingredient has a specific particle size distribution, the active ingredient can reach the recipient's respiratory tissue, particularly the upper respiratory tract and lungs, and therefore has a high and long-lasting anti-tumor properties. Influenza activity is maintained.
　本発明のネブライザー用組成物は、受容者に投与する際、等張液とするので、呼吸器組織への刺激が軽減されている。 Since the nebulizer composition of the present invention is an isotonic solution when administered to a recipient, irritation to respiratory tissue is reduced.
　これまで、吸入液剤を凍結乾燥製剤としたものは知られていない。本発明の凍結乾燥製剤は、物理的安定性に優れており、常温常圧で６ヶ月以上保存した該凍結乾燥製剤を用いて調製した本発明のネブライザー用組成物は、優れた噴霧性を示す。 So far, no lyophilized preparation of inhalation solution has been known. The freeze-dried preparation of the present invention is excellent in physical stability, and the nebulizer composition of the present invention prepared using the freeze-dried preparation stored at normal temperature and pressure for 6 months or more exhibits excellent sprayability. .
　本発明のネブライザー用組成物の有効成分であるラニナミビルオクタン酸エステル水和物、またはその薬理上許容される塩は、国際公開第２００８／１２６９４３号パンフレット、或いは、国際公開第２０１３／０８９１６８号パンフレットに開示された方法又はそれに準ずる方法に従って製造することができる。 The laninamivir octanoic acid ester hydrate, which is an active ingredient of the nebulizer composition of the present invention, or a pharmacologically acceptable salt thereof is disclosed in WO2008 / 126943 or WO2013 / 089168. It can be produced according to the method disclosed in the pamphlet or a method analogous thereto.
　本発明のネブライザー用組成物の有効成分は、前述したように、レーザー回折散乱式粒度分布測定法による５０重量％の有効成分の粒子径が５．０μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法による９０重量％の有効成分の粒子径が１２．０μｍ以下であることが好ましい。さらに、レーザー回折散乱式粒度分布測定法による５０重量％の有効成分の粒子径が３．２μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法による９０重量％の有効成分の粒子径が８．０μｍ以下であることが、より好ましい。このような粒子径のラニナミビルオクタン酸エステル水和物、またはその薬理上許容される塩は、国際公開第２００８／１２６９４３号パンフレット、或いは、国際公開第２０１３／０８９１６８号パンフレットに開示された方法又はそれに準ずる方法に従って製造することができる。 As described above, the effective component of the nebulizer composition of the present invention has a particle size of 50% by weight or less of the active component measured by the laser diffraction / scattering particle size distribution measurement method of 5.0 μm or less, and the laser diffraction / scattering particle size. The particle diameter of 90% by weight of the active ingredient is preferably 12.0 μm or less by the distribution measurement method. Further, the particle diameter of 50% by weight of the active ingredient according to the laser diffraction / scattering particle size distribution measurement method is 3.2 μm or less, and the particle diameter of 90% by weight of the active ingredient according to the laser diffraction / scattering particle size distribution measurement method is 8 It is more preferable that it is 0.0 μm or less. The laninamivir octanoic acid ester hydrate having such a particle size, or a pharmacologically acceptable salt thereof, is a method disclosed in International Publication No. 2008/126943 pamphlet or International Publication No. 2013/089168 pamphlet. Or it can manufacture according to the method according to it.
　本発明の凍結乾燥製剤は、以下に述べる方法によって製造することができる。 The lyophilized preparation of the present invention can be produced by the method described below.
　上述の国際公報に開示された方法又はそれに準ずる方法により所定の粒子径として製造された有効成分を、ジェットミル等の乾式粉砕法により微粒子化する。ついで、微粒子化した有効成分を、分散剤と浸透圧調節剤を溶解させて得られた溶液に合わせ、ヒスコトロン等のホモジナイザーや、エマルシフレックス、マイクロフルイダイザー等の高圧ホモジナイザーによって有効成分の微粒子を分散させ、ついで得られた混合液を容器に充填し、凍結乾燥させて凍結乾燥製剤とする。 The active ingredient produced as a predetermined particle diameter by the method disclosed in the above-mentioned international publication or a method according thereto is made into fine particles by a dry pulverization method such as a jet mill. Next, the finely divided active ingredient is combined with the solution obtained by dissolving the dispersant and the osmotic pressure regulator, and the active ingredient fine particles are mixed with a homogenizer such as Hiscotron or a high-pressure homogenizer such as emulflex or microfluidizer. Disperse, then fill the resulting mixture into a container and lyophilize to form a lyophilized formulation.
　あるいは、微粒子化した有効成分と、分散剤を精製水に溶解したものとを合わせ、ヒスコトロン等のホモジナイザーや、エマルシフレックス、マイクロフルイダイザー等の高圧ホモジナイザーによって有効成分の微粒子を分散させる。ついで得られた懸濁液を容器に充填し、凍結乾燥させて凍結乾燥製剤とする。 Alternatively, the finely divided active ingredient is combined with a dispersant dissolved in purified water, and the active ingredient fine particles are dispersed by a homogenizer such as Hiscotron or a high-pressure homogenizer such as emulflex or microfluidizer. The resulting suspension is then filled into a container and lyophilized to form a lyophilized formulation.
　この方法は、凍結乾燥製剤中に有効成分と分散剤のみを含む場合に用いられる製造方法である。 This method is a production method used when a freeze-dried preparation contains only an active ingredient and a dispersant.
　このようにして製造された本発明の凍結乾燥製剤は、封入されている容器に、懸濁用液を加えて分散することにより、ネブライザー用組成物として調製される。 The lyophilized preparation of the present invention thus produced is prepared as a nebulizer composition by adding and dispersing a suspension liquid in an enclosed container.
　凍結乾燥製剤に、有効成分、分散剤、浸透圧調節剤が含まれる場合は、懸濁用液は精製水が好ましい。 精製 When the lyophilized preparation contains an active ingredient, a dispersant, and an osmotic pressure regulator, the suspension liquid is preferably purified water.
　凍結乾燥製剤に、有効成分と分散剤のみが含まれる場合には、懸濁用液として浸透圧調節剤の水溶液が用いられる。具体例として、塩化ナトリウムの水溶液、或いは、生理食塩水が挙げられる。 When the freeze-dried preparation contains only the active ingredient and the dispersant, an aqueous solution of an osmotic pressure regulator is used as the suspension liquid. Specific examples include an aqueous solution of sodium chloride or physiological saline.
　このようにして製造される本発明のネブライザー用組成物は、懸濁液状の水性液剤である。 The nebulizer composition of the present invention thus produced is a suspension-like aqueous liquid preparation.
　このようにして製造された本発明のネブライザー用組成物は、ネブライザー、好ましくはジェット式ネブライザー（コンプレッサー式ネブライザーとも呼ばれる）を用いて、受容者に投与される。 The nebulizer composition of the present invention thus produced is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
　本発明のネブライザー用組成物の投与量は、ラニナミビルオクタン酸エステルを無水物換算で、１回の投与につき、好ましくは４０～３２０ｍｇ、より好ましくは８０～１６０ｍｇ、特に好ましくは１６０ｍｇである。 The dose of the nebulizer composition of the present invention is preferably 40 to 320 mg, more preferably 80 to 160 mg, and particularly preferably 160 mg per administration of laninamivir octanoate in terms of anhydride.
　本発明のネブライザー用組成物の投与量は、具体的には、ラニナミビルオクタン酸エステルを無水物換算で、１回の投与につき、例えば、８０ｍｇ、１６０ｍｇ、２４０ｍｇ、３２０ｍｇであり、好ましくは８０ｍｇ、１６０ｍｇであり、特に好ましくは１６０ｍｇである。 Specifically, the dosage of the composition for nebulizer of the present invention is, for example, 80 mg, 160 mg, 240 mg, 320 mg, preferably 80 mg per one administration of laninamivir octanoic acid ester in terms of anhydride. 160 mg, particularly preferably 160 mg.
　本発明のネブライザー用組成物をインフルエンザウイルス感染症の予防剤として投与する場合は、インフルエンザウイルス感染症の発症前のヒトの呼吸器組織に、間歇的に投与する。１回の投与につき、上述の投与量を吸入する。投与間隔は例えば、５～１０日、あるいは、１週間である。 When the nebulizer composition of the present invention is administered as a preventive agent for influenza virus infection, it is intermittently administered to human respiratory tissue before the onset of influenza virus infection. For each dose, the above dose is inhaled. The administration interval is, for example, 5 to 10 days or 1 week.
　ここで、発症前とは、ウイルス感染の有無は問わず、インフルエンザ症状が認められない状態のことをいう。 Here, “before onset” means a state in which no influenza symptoms are observed regardless of the presence or absence of viral infection.
　実際の医療の現場では、インフルエンザウイルスに感染したか否かに係らず、インフルエンザ症状を発症する前に投与することを予防投与とする場合がある。本発明の予防剤の投与時期には、感染の有無に係らず、発症前に投与することも包含される。 In actual medical settings, administration before the onset of influenza symptoms may be a preventive administration, regardless of whether or not the patient has been infected with influenza virus. The administration time of the prophylactic agent of the present invention includes administration before onset regardless of the presence or absence of infection.
　本発明のネブライザー用組成物をインフルエンザウイルス感染症の治療剤として投与する場合は、インフルエンザウイルス感染症の発症時のヒトの呼吸器組織に、１回の投与により上述の投与量を吸入する。 When administering the nebulizer composition of the present invention as a therapeutic agent for influenza virus infection, the above dose is inhaled into a human respiratory tissue at the onset of influenza virus infection by a single administration.
　発症時とは、インフルエンザウイルスが感染し、発熱等の自覚症状が認められることをいう。 “At onset” means that the influenza virus is infected and subjective symptoms such as fever are observed.
　吸入液剤の投与に際しては、吸入用装置であるネブライザーが必要であり、そのような装置を所持していない受容者でも、本発明のネブライザー用組成物は、１回で投与が完結するため、繰り返し病院に通う必要がなく、受容者の通院による負担が少なくてもすむ。１回の投与で治療が完了することから、現在市販されているノイラミニダーゼ阻害剤の中で、ネブライザーとの組合せが製品として成り立つのはラニナミビルオクタン酸エステル水和物のみである。 When administering an inhalation solution, a nebulizer, which is an inhalation device, is required, and even a recipient who does not have such a device repeats the nebulizer composition of the present invention because administration is completed once. There is no need to go to the hospital, and the recipient's visit to the hospital is less burdensome. Since the treatment is completed with a single administration, only the laninamivir octanoate hydrate is the only neuraminidase inhibitor currently on the market that can be combined with a nebulizer as a product.
　以下に実施例及び試験例を示し、本発明を更に詳細に説明する。
（実施例１～３）　ネブライザー用組成物の製造
　国際公開第２００８／１２６９４３号に記載の製造方法に準じて製造したラニナミビルオクタン酸エステル水和物の結晶（以下、有効成分という。）をジェットミル法（超音速ジェット粉砕機（型式ＰＪＭ－１００ＳＰ）、日本ニューマチック工業株式会社）で粉砕し、表１に示す粒子径分布の粉砕物を得た。　　 The following examples and test examples illustrate the present invention in more detail.
(Examples 1 to 3) Manufacture of a composition for nebulizer Crystals of laninamivir octanoate hydrate produced according to the production method described in International Publication No. 2008/126943 (hereinafter referred to as an active ingredient). The mixture was pulverized by a jet mill method (supersonic jet pulverizer (type PJM-100SP), Nippon Pneumatic Industry Co., Ltd.) to obtain a pulverized product having a particle size distribution shown in Table 1.
　次に、分散剤として所定量のヒドロキシプロピルメチルセルロースを、浸透圧調節剤として乳糖水和物あるいは塩化ナトリウムを精製水に溶解したものと、所定量の有効成分と合わせて、ホモジナイザー（ヒスコトロン（型式：ＮＳ－５０）、(株)日音医理科器械製作所）で予分散し、ついで、高圧ホモジナイザー（マイクロフルイダイザー（型式：Ｍ－１１０ＥＨ）、株式会社パウレック）で分散し、実施例１～３の懸濁液状の組成物得た。得られた組成を表２に示す。 Next, a homogenizer (Hiscotron (model :): a combination of a predetermined amount of hydroxypropylmethylcellulose as a dispersant, lactose hydrate or sodium chloride dissolved in purified water as an osmotic pressure regulator, and a predetermined amount of active ingredient. NS-50), pre-dispersed by Nissin Medical Science Co., Ltd., and then dispersed by a high-pressure homogenizer (microfluidizer (model: M-110EH), Powrec Co., Ltd.). A suspension-like composition was obtained. The resulting composition is shown in Table 2.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000004
 　＊１：有効成分の無水物としての重量を表す
Figure JPOXMLDOC01-appb-T000004
 * 1: Indicates the weight of the active ingredient as an anhydride.
（実施例４、５）　ネブライザー用組成物の製造
　分散剤として所定量のポリオキシエチレンソルビタンモノラウレート（ツイーン２０）、ソルビタンモノラウレート（スパン２０）及び塩化ナトリウムを精製水に溶解し、所定量の粉砕した有効成分と合わせて、ホモジナイザー（ヒスコトロン）（ＮＳ－５０、（株）日音医理科器械製作所）で予分散し、ついで、マイクロフルイダイザー（Ｍ－１１０ＥＨ、株式会社パウレック）で分散し、実施例４、５の懸濁液状の組成物を得た。得られた組成を表３に示す。 (Examples 4 and 5) Manufacture of a composition for a nebulizer A predetermined amount of polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (span 20) and sodium chloride were dissolved in purified water as a dispersant. Pre-dispersed with a homogenizer (Hiscotron) (NS-50, Nissin Medical Science Instrument Co., Ltd.), and then dispersed with a microfluidizer (M-110EH, Paulek Co., Ltd.) As a result, suspension-like compositions of Examples 4 and 5 were obtained. The resulting composition is shown in Table 3.
Figure JPOXMLDOC01-appb-T000005
 　＊１：有効成分の無水物としての重量を表す
Figure JPOXMLDOC01-appb-T000005
 * 1: Indicates the weight of the active ingredient as an anhydride.
（比較例１）イナビル（商標名）吸入粉末剤を精製水で分散した組成物
　市販されているイナビル（商標名）吸入粉末剤２０ｍｇは、ラニナミビルオクタン酸エステル水和物と乳糖水和物とからなる組成物である。この粉末を４００ｍｇ取り、精製水８ｍＬにて分散し、比較例１の組成物を得た。得られた組成を表４に示す。この粉末４００ｍｇ中、ラニナミビルオクタン酸エステル水和物を無水物として８０ｍｇ含む。 (Comparative Example 1) Composition in which Inavir (trade name) inhalation powder was dispersed in purified water 20 mg of Inavir (trade name) inhalation powder commercially available was laninamivir octanoate hydrate and lactose hydrate It is a composition which consists of. 400 mg of this powder was taken and dispersed in 8 mL of purified water to obtain the composition of Comparative Example 1. Table 4 shows the obtained composition. In 400 mg of this powder, 80 mg of laninamivir octanoate hydrate as an anhydride is contained.
Figure JPOXMLDOC01-appb-T000006
 ＊１：有効成分を無水物として８０ｍｇ含む
Figure JPOXMLDOC01-appb-T000006
 * 1: Contains 80 mg of active ingredient as an anhydride
（比較例２～３）分散剤のみの組成物
　分散剤としてポリオキシエチレンソルビタンモノオレエート（ツイーン８０）及び／又はカルボキシメチルセルロースナトリウム（ＣＭＣＮａ）を精製水に溶解し、所定量の粉砕した有効成分とあわせてホモジナイザー（ヒスコトロン（型式：ＮＳ－５０）、（株)日音医理科器械製作所）で予分散し、ついで、高圧ホモジナイザー（マイクロフルイダイザー（型式：Ｍ－１１０ＥＨ）、株式会社パウレック）で分散し、懸濁液状の組成物を得た。得られた組成を表５に示す。 (Comparative Examples 2 to 3) Composition containing only a dispersant As a dispersant, polyoxyethylene sorbitan monooleate (Tween 80) and / or sodium carboxymethylcellulose (CMCNa) is dissolved in purified water, and a predetermined amount of the pulverized active ingredient And pre-dispersed with a homogenizer (Hiscotron (model: NS-50), Nissin Medical Science Mfg. Co., Ltd.), followed by a high-pressure homogenizer (microfluidizer (model: M-110EH), POWREC Co., Ltd.) Dispersion was performed to obtain a suspension-like composition. The obtained composition is shown in Table 5.
Figure JPOXMLDOC01-appb-T000007
 ＊１：有効成分の無水物としての重量を表す
Figure JPOXMLDOC01-appb-T000007
 * 1: Indicates the weight of the active ingredient as an anhydride.
（実施例６、７）　ネブライザー用組成物と凍結乾燥製剤の製造
　分散剤として所定量のチロキサポールを、浸透圧調節剤として所定量の塩化ナトリウムを精製水に溶解したものに混合し、所定量の粉砕した有効成分と合わせて、攪拌機（ＭＡＺＥＬＡ　Ｚ（型式：Ｚ－１１００）、ＥＹＥＬＡ）で予分散し、ついで、高圧ホモジナイザー（マイクロフルイダイザー（型式：Ｈ－１１０ＥＨ）、株式会社パウレック）で分散し、実施例６の懸濁液状の組成物を得た。また、得られた組成物を凍結乾燥機（Ｔｒｉｏｍａｓｔｅｒ　ＩＩ　Ａ－０４、共和真空）を用いて凍結乾燥し、実施例７の凍結乾燥製剤を得た。得られた製剤の組成を表６に示す。 (Examples 6 and 7) Preparation of nebulizer composition and lyophilized preparation A predetermined amount of tyloxapol as a dispersant and a predetermined amount of sodium chloride dissolved in purified water as an osmotic pressure regulator are mixed together. Combined with the pulverized active ingredient, pre-dispersed with a stirrer (MAZELA Z (model: Z-1100), EYELA), then dispersed with a high-pressure homogenizer (microfluidizer (model: H-110EH), POWREC Co., Ltd.) A suspension-like composition of Example 6 was obtained. The obtained composition was lyophilized using a lyophilizer (Trimaster II A-04, Kyowa Vacuum) to obtain a lyophilized preparation of Example 7. Table 6 shows the composition of the obtained preparation.
Figure JPOXMLDOC01-appb-T000008
 　＊１：有効成分の無水物としての重量を表す
　＊２：工程中に除去される
Figure JPOXMLDOC01-appb-T000008
 * 1: Represents the weight of the active ingredient as an anhydride * 2: Removed during the process
（実施例８～１４）　ネブライザー用凍結乾燥製剤の製造
　分散剤として所定量のチロキサポールを精製水に溶解し、所定量の粉砕した有効成分と合わせて、攪拌機（ＭＡＺＥＬＡ　Ｚ（型式：Ｚ－１１００）、ＥＹＥＬＡ）で予分散し、ついで、高圧ホモジナイザー（圧力式ホモジナイザー（型式：ＬＡＢ１０００）、株式会社エスエムテー）で分散し、得られた混合物を凍結乾燥機（Ｔｒｉｏｍａｓｔｅｒ　ＩＩＡ－０４、共和真空）を用いて凍結乾燥して、実施例８～１４の凍結乾燥製剤を得た。得られた凍結乾燥製剤の組成を表７に示す。 (Examples 8 to 14) Production of lyophilized preparation for nebulizer A predetermined amount of tyloxapol as a dispersing agent was dissolved in purified water, combined with a predetermined amount of pulverized active ingredient, and a stirrer (MAZELA Z (model: Z-1100) , EYELA), and then dispersed with a high-pressure homogenizer (pressure homogenizer (model: LAB1000), SMT Co., Ltd.). Lyophilized to obtain freeze-dried preparations of Examples 8-14. Table 7 shows the composition of the obtained freeze-dried preparation.
Figure JPOXMLDOC01-appb-T000009
 　＊１：有効成分の無水物としての重量を表す
　＊２：工程中に除去される
Figure JPOXMLDOC01-appb-T000009
 * 1: Represents the weight of the active ingredient as an anhydride * 2: Removed during the process
（実施例１５～２２）　ネブライザー用組成物の調製
　実施例７で得られた凍結乾燥製剤に精製水を、実施例８～１４で得られた凍結乾燥製剤に生理食塩水を加え分散して、実施例１５～２２のネブライザー用組成物を得た。得られた組成を表８に示す。 (Examples 15 to 22) Preparation of composition for nebulizer Purified water was added to the lyophilized preparation obtained in Example 7, and physiological saline was added to the lyophilized preparation obtained in Examples 8 to 14, and dispersed. The nebulizer compositions of Examples 15 to 22 were obtained. Table 8 shows the obtained composition.
Figure JPOXMLDOC01-appb-T000010
 ＊１：有効成分を無水物として８０ｍｇ含む
＊２：懸濁用液２ｍＬにて分散
Figure JPOXMLDOC01-appb-T000010
 * 1: Contains 80 mg of the active ingredient as an anhydride * 2: Dispersed in 2 mL of suspension liquid
（実施例２３～２５）有効成分含量違いの組成物の調製
　実施例９の凍結乾燥製剤を生理食塩水４ｍＬで分散したもののうち、２ｍＬをネブライザーに注入して有効成分を４０ｍｇ含有する製剤としたものを実施例２３、実施例９の凍結乾燥製剤を生理食塩水１ｍＬで分散したものを２本あわせてネブライザーに注入したものを実施例２４、実施例９の凍結乾燥製剤を生理食塩水０．５ｍＬにて分散したものを４本あわせてネブライザーに注入したものを実施例２５として、ネブライザー用の吸入液剤を得た。なお、有効成分量は無水物としての重量を示す。得られた組成を表９に示す。 (Examples 23 to 25) Preparation of compositions having different active ingredient contents Of the lyophilized preparation of Example 9 dispersed in 4 mL of physiological saline, 2 mL was injected into a nebulizer to obtain a preparation containing 40 mg of the active ingredient. Two of the lyophilized preparations of Example 23 and Example 9 dispersed in 1 mL of physiological saline and injected into a nebulizer were combined in Example 24, and the lyophilized preparation of Example 9 was added to physiological saline 0. An inhalation liquid for nebulizer was obtained as Example 25, in which four dispersed in 5 mL were poured into a nebulizer. The amount of active ingredient indicates the weight as an anhydride. Table 9 shows the obtained composition.
Figure JPOXMLDOC01-appb-T000011
 ＊１：有効成分を無水物として８０ｍｇ含む
＊２：有効成分の無水物としての重量を表す
Figure JPOXMLDOC01-appb-T000011
 * 1: Contains 80 mg of the active ingredient as an anhydride * 2: Indicates the weight of the active ingredient as an anhydride
（実施例２６～２８）ネブライザー用凍結乾燥製剤の製造
　分散剤として所定量のチロキサポールを精製水に溶解し、ジェットミル法（超音速ジェット粉砕機（型式ＰＪＭ－１００ＳＰ）、日本ニューマチック工業株式会社）で粉砕した所定量の有効成分と合わせて、攪拌機（シールミキサー（型式：RC-60G5-2S）、マグネオ技研）で予分散し、ついで、高圧ホモジナイザー（圧力式ホモジナイザー（型式：R5-10.38）、株式会社エスエムテー）で分散し、得られた混合物を凍結乾燥機（凍結真空乾燥装置（型式DFB3055-2BS-ST/CIP）、株式会社アルバック）を用いて凍結乾燥して、実施例２６～２８の凍結乾燥製剤を得た。得られた凍結乾燥製剤の組成を表１０に示す。 (Examples 26 to 28) Production of lyophilized preparation for nebulizer A predetermined amount of tyloxapol as a dispersant was dissolved in purified water, and the jet mill method (supersonic jet crusher (model PJM-100SP), Nippon Pneumatic Industry Co., Ltd.) ) And pre-dispersed with a stirrer (seal mixer (model: RC-60G5-2S), Magneo Giken), followed by high-pressure homogenizer (pressure homogenizer (model: R5-10.38) The resulting mixture was freeze-dried using a freeze dryer (freeze vacuum dryer (model DFB3055-2BS-ST / CIP), ULVAC, Inc.), and Examples 26 to 28 were dispersed. A freeze-dried preparation was obtained. Table 10 shows the composition of the obtained freeze-dried preparation.
Figure JPOXMLDOC01-appb-T000012
 ＊１：有効成分の無水物としての重量を示す。
＊２：工程中に除去される
Figure JPOXMLDOC01-appb-T000012
 * 1: Indicates the weight of the active ingredient as an anhydride.
* 2: Removed during the process
（実施例２９～３５）有効成分含量違いの組成物の調製
　実施例２６の凍結乾燥製剤を生理食塩水４ｍＬで分散したもののうち、２ｍＬをネブライザーに注入し、有効成分を４０ｍｇ含有するネブライザー用組成物としたものを実施例２９、実施例２６の凍結乾燥製剤を生理食塩水２ｍＬで分散してネブライザーに注入し、有効成分を８０ｍｇ含有するネブライザー用組成物としたものを実施例３０、　
実施例２６の凍結乾燥製剤を生理食塩水１ｍＬで分散したものを２本あわせてネブライザーに注入し、有効成分を１６０ｍｇ含有するネブライザー用組成物としたものを実施例３１、実施例２６の凍結乾燥製剤を生理食塩水１ｍＬで分散したものを３本あわせてネブライザーに注入し、有効成分を２４０ｍｇ含有するネブライザー用組成物としたものを実施例３２、実施例２６の凍結乾燥製剤を生理食塩水１ｍＬで分散したものを４本あわせてネブライザーに注入し、有効成分を３２０ｍｇ含有するネブライザー用組成物としたものを実施例３３、実施例２７の結乾燥製剤を生理食塩水２ｍＬで分散してネブライザーに注入し、有効成分を８０ｍｇ含有するネブライザー用組成物としたものを実施例３４、実施例２８の結乾燥製剤を生理食塩水２ｍＬで分散してネブライザーに注入し、有効成分を１６０ｍｇ含有するネブライザー用組成物としたものを実施例３５とした。なお、有効成分量は無水物としての重量を示す。得られた組成を表１１に示す。 (Examples 29 to 35) Preparation of composition with different active ingredient content Among the lyophilized preparation of Example 26 dispersed in 4 mL of physiological saline, 2 mL was injected into the nebulizer and the composition for nebulizer containing 40 mg of the active ingredient What was prepared as Example 29, the freeze-dried preparation of Example 26 was dispersed in 2 mL of physiological saline and injected into a nebulizer to prepare a nebulizer composition containing 80 mg of the active ingredient in Example 30,
Two of the freeze-dried preparations of Example 26 dispersed in 1 mL of physiological saline were poured into a nebulizer and the nebulizer composition containing 160 mg of the active ingredient was used as the freeze-dried examples 31 and 26. Three of the preparations dispersed in 1 mL of physiological saline were combined and injected into a nebulizer to prepare a nebulizer composition containing 240 mg of the active ingredient. The lyophilized preparations of Example 32 and Example 26 were added to 1 mL of physiological saline. Four of those dispersed in (1) were poured into a nebulizer, and the nebulizer compositions containing 320 mg of the active ingredient were dispersed in 2 ml of physiological saline in Example 33 and Example 27, and the nebulizer was dispersed in the nebulizer. The nebulizer composition containing 80 mg of the active ingredient was injected into the dried preparations of Example 34 and Example 28 as physiological saline. Was injected into the nebulizer dispersed in 2 mL, the active ingredient was as in Example 35 to those with nebulizer composition containing 160 mg. The amount of active ingredient indicates the weight as an anhydride. The obtained composition is shown in Table 11.
Figure JPOXMLDOC01-appb-T000013
 ＊１：１バイアル中の有効成分の無水物としての重量を表す
＊２：有効成分の無水物としての重量を表す
Figure JPOXMLDOC01-appb-T000013
 * 1: Represents the weight of the active ingredient as an anhydride in a vial. * 2: Represents the weight of the active ingredient as an anhydride.
（試験方法）　薬剤の呼吸器到達性評価（微粒子量の測定法）
　吸入液剤の呼吸器到達性をインビトロで簡易的に評価する方法として、next generation impactor（NGI）による微粒子量の測定法が汎用されている（例えば、USP37、<1601> products for nebulization- characterization testsや、European Pharmacopoeia 7.3、2.9.44. preparations for nebulization: characterisation参照）。 (Test method) Respiratory reachability evaluation of drug (Measurement method of fine particle amount)
As a method for simple evaluation of inhalation solution reachability in the respiratory tract in vitro, a method for measuring the amount of fine particles using the next generation impactor (NGI) is widely used (for example, USP37, <1601> products for nebulization-characterization tests and , European Pharmacopoeia 7.3, see 2.9.44. Preparations for nebulization: characterisation).
　この方法は吸入用器具からポンプを介してインパクター内に吸引導入された薬剤粒子を分級する装置を用いる。吸引された薬剤は粒子径に応じてインパクターを構成する１０個のパーツ（マウスピースアダプター、インダクションポート、ステージ1～7、マイクロオリフィスコレクター（ＭＯＣ））のいずれかに到達する。凝集塊等の大きな粒子はマウスピースアダプター、インダクションポートに捕集される。一方、粒子径の細かい薬剤粒子は、ステージ1～MOCのいずれかに到達するが、粒子径が小さいほど番号の大きいステージに到達し、ステージ７を通過した薬剤粒子はＭＯＣに捕集される。 This method uses a device that classifies drug particles sucked into the impactor through a pump from an inhaler. The aspirated medicine reaches any one of 10 parts (mouthpiece adapter, induction port, stages 1 to 7, micro-orifice collector (MOC)) constituting the impactor according to the particle diameter. Large particles such as agglomerates are collected in the mouthpiece adapter and induction port. On the other hand, drug particles with a small particle size reach any one of stages 1 to MOC, but the smaller the particle size, the higher the numbered stage, and the drug particles that have passed through stage 7 are collected by MOC.
　薬剤の粒子径とガンマシンチグラフィーで測定された薬剤の呼吸器官への送達量との相関性を調べた文献（Newman SP, Chan HK. In Vitro/In Vivo Comparisons in Pulmonary Drug Delivery. J Aerosol、Glover W, Chan HK, Eberl S, et al. Lung Deposition of Mannitol Powder Aerosol in Healthy Subjects. J Aerosol Med. 2006;19:522-532. Med Pulm Drug Deliv. 2008;21:77-84.）によると、粒子径３μｍ乃至５μｍ 以下の薬剤の量は、薬剤の呼吸器官への送達量と相関する。本発明のネブライザー用組成物では含有される有効成分量のうち空力学的粒子径が４．４μｍ以下の有効成分量を微粒子量（ファインパーティクルドーズ：ＦＰＤ）と定義し、このパラメーターを用いて呼吸器到達性を評価した。 Literature investigating the correlation between drug particle size and the amount of drug delivered to the respiratory tract measured by gunmachigraphy (Newman SP, Chan HK. In Vitro / In Vivo Comparisons in Pulmonary Drug Delivery. J Aerosol, Glover W, Chan HK, Eberl S, et al. Lung Deposition of Mannitol Powder Aerosol in Healthy Subjects. J Aerosol Med. 2006; 19: 522-532. Med Pulm Drug Deliv. 2008; 21: 77-84. The amount of drug with a particle size of 3 μm to 5 μm or less correlates with the amount of drug delivered to the respiratory tract. In the nebulizer composition of the present invention, the amount of active ingredient having an aerodynamic particle size of 4.4 μm or less is defined as the amount of fine particles (fine particle dose: FPD) out of the amount of active ingredient contained, and breathing is performed using this parameter. The vessel reachability was evaluated.
　この評価は微粒子量の評価であるため、以下の試験例では、微粒子量評価とも記載する。なお、各種ネブライザー用組成物の噴霧は、コンプレッサー式ネブライザー装置（コンプレッサー：パリ・ボーイＮ（ＰＡＲＩ　Ｊａｐａｎ）、ネブライザー：パリ・ＬＣプラス（ＰＡＲＩ　Ｊａｐａｎ））を用いて行った。 Since this evaluation is an evaluation of the amount of fine particles, it is also referred to as an evaluation of the amount of fine particles in the following test examples. In addition, spraying of the composition for various nebulizers was performed using a compressor type nebulizer device (compressor: Paris Boy N (PARI Japan), nebulizer: Paris LC plus (PARI Japan)).
（試験例１）イナビル吸入粉末剤を精製水で分散した場合の微粒子量評価
　イナビル吸入粉末剤２０ｍｇの粉末４００ｍｇ（有効成分を無水物として８０ｍｇ含む）を精製水８ｍＬにて分散した液の微粒子量評価を行った結果を表１２に示す。微粒子量（ＦＰＤ）はわずか０．４ｍｇであった。 (Test Example 1) Evaluation of the amount of fine particles when the inavir inhalation powder is dispersed in purified water The amount of fine particles in a liquid in which 400 mg of 20 mg of inavir inhalation powder (containing 80 mg of the active ingredient as an anhydride) is dispersed in 8 ml of purified water Table 12 shows the results of the evaluation. The amount of fine particles (FPD) was only 0.4 mg.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
（試験例２）分散剤のみの懸濁液
　比較例２及び３で得られた組成物の微粒子量評価結果を表１３に示す。 (Test Example 2) Suspension only suspension Table 13 shows the evaluation results of the amount of fine particles of the compositions obtained in Comparative Examples 2 and 3.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
（試験例３）浸透圧調節剤の影響
　実施例１～３で得られた組成物の微粒子量評価結果を表１４に示す。分散剤ヒドロキシプロピルメチルセルロースに加えて、乳糖水和物あるいは塩化ナトリウムを添加することで、良好な微粒子量を示した。 (Test Example 3) Effect of osmotic pressure regulator Table 14 shows the evaluation results of the amount of fine particles of the compositions obtained in Examples 1 to 3. The addition of lactose hydrate or sodium chloride in addition to the dispersant hydroxypropylmethylcellulose showed a good fine particle amount.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
（試験例４）分散剤の影響
　試験例３と同様にして、実施例４、５で得られた、分散剤としてポリオキシエチレンソルビタンモノラウレート（ツイーン２０）及びソルビタンモノラウレート（スパン２０）を添加した組成物について微粒子量を評価した。結果を表１５に示す。分散剤として両物質を添加した系においても、良好な微粒子量を示した。 (Test Example 4) Influence of Dispersant As in Test Example 3, polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (span 20) obtained in Examples 4 and 5 were used as dispersants. The amount of fine particles was evaluated for the composition to which was added. The results are shown in Table 15. Even in a system in which both substances were added as a dispersant, a good amount of fine particles was shown.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
（試験例５）　凍結乾燥製剤の微粒子量評価
　分散剤としてチロキサポールを、浸透圧調節剤として塩化ナトリウムの水溶液を配合する組成物を調製し、懸濁液の状態（実施例６）と凍結乾燥製剤を精製水に分散した状態（実施例１５）の微粒子量を評価した。結果を表１６に示す。懸濁液として製造した組成物、及び凍結乾燥後に塩化ナトリウムの水溶液にて分散させた組成物、ともに良好な微粒子量を示した。 (Test Example 5) Fine particle amount evaluation of lyophilized preparation A composition containing tyloxapol as a dispersant and an aqueous solution of sodium chloride as an osmotic pressure regulator was prepared, and the suspension state (Example 6) and lyophilized preparation were prepared. Was evaluated for the amount of fine particles dispersed in purified water (Example 15). The results are shown in Table 16. Both the composition produced as a suspension and the composition dispersed in an aqueous solution of sodium chloride after lyophilization showed a good fine particle amount.
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
（試験例６）凍結乾燥製剤の安定性評価
　実施例７の凍結乾燥製剤の安定性評価を行った。微粒子量の評価は実施例１５と同じ方法でネブライザー用組成物とし、上述の方法で行った。不純物の評価はＨＰＬＣ法により行った。結果を表１７に示す。本剤は、６ヵ月まで安定であることが確認された。 (Test Example 6) Stability evaluation of freeze-dried preparation The stability evaluation of the freeze-dried preparation of Example 7 was performed. The amount of fine particles was evaluated by the same method as in Example 15 to obtain a nebulizer composition. Impurities were evaluated by the HPLC method. The results are shown in Table 17. This drug was confirmed to be stable up to 6 months.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
（試験例７）種々のチロキサポール配合量と種々の粒子径を有する有効成分を含む組成物の微粒子量評価
　分散剤としてチロキサポールを含有する組成物で、有効成分の粒子径を変化させた場合の微粒子量を評価した。結果を表１８に示す。本実施例でのチロキサポール量と有効成分の粒子径の範囲では良好な微粒子量を示した。 (Test Example 7) Fine particle amount evaluation of a composition containing an active ingredient having various amounts of tyloxapol and various particle diameters Fine particles obtained by changing the particle diameter of an active ingredient in a composition containing tyloxapol as a dispersant The amount was evaluated. The results are shown in Table 18. A good fine particle amount was shown in the range of the amount of tyloxapol and the particle diameter of the active ingredient in this example.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
（試験例８）
　実施例９で得られた凍結乾燥製剤を精製水で分散したものを比較例４として、実施例１７で得られた組成物と微粒子量を比較した。結果を表１９に示す。浸透圧調節剤として塩化ナトリウムを添加することで、微粒子量が向上することが示された。 (Test Example 8)
The lyophilized preparation obtained in Example 9 was dispersed in purified water as Comparative Example 4, and the composition obtained in Example 17 and the amount of fine particles were compared. The results are shown in Table 19. It was shown that the amount of fine particles was improved by adding sodium chloride as an osmotic pressure regulator.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
（試験例９）
　実施例１７、実施例２３～２５、実施例３０、および、実施例３４～３５の微粒子量評価結果を表２０に示す。有効成分含量の増加に伴い、ＦＰＤも増加することが示された。 (Test Example 9)
Table 20 shows the particle amount evaluation results of Example 17, Examples 23 to 25, Example 30, and Examples 34 to 35. It has been shown that FPD increases with increasing active ingredient content.
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
（試験例１０）健康成人男性対象の薬物動態の検討試験
　日本人健康成人男性を対象として、有効成分を含有するネブライザー用組成物をネブライザーを用いて単回吸入投与し、有効成分、及び、有効成分の活性代謝物である前述の化合物（ＩＩＩ）（以下、活性代謝物とも記す）の血漿中及び肺胞内の薬物動態を検討した。 (Test Example 10) Pharmacokinetic study test of healthy adult male subjects A single nebulizer composition containing an active ingredient was administered by inhalation using a nebulizer for Japanese healthy adult male subjects. The pharmacokinetics of the compound (III) (hereinafter also referred to as active metabolite), which is an active metabolite of the component, in plasma and alveoli were examined.
　有効成分の吸入投与前後に採血を行い、血漿中の薬物濃度を測定した。また、有効成分を吸入投与後に肺胞内洗浄を行い、肺胞粘液及び肺胞マクロファージ中の薬物濃度を測定した。薬物濃度は、有効成分及び活性代謝物を対象として行った。薬物濃度の測定には、バリデーションされた液体クロマトグラフィータンデムマススペクトロメトリー法を用いた。 Blood was collected before and after inhalation of the active ingredient, and the drug concentration in plasma was measured. In addition, the alveolar lavage was performed after administration of the active ingredient by inhalation, and the drug concentrations in alveolar mucus and alveolar macrophages were measured. The drug concentration was measured for active ingredients and active metabolites. A validated liquid chromatography tandem mass spectrometry method was used for drug concentration measurements.
　血漿中薬物動態のみを評価する場合、投薬は、有効成分（無水物としての重量を示す。以下、試験例１０において同様である。）として、４０ｍｇ、８０ｍｇ、１６０ｍｇ、２４０ｍｇ、又は３２０ｍｇを単回投与した。投薬には、それぞれ、実施例２９、実施例３０、実施例３１、実施例３２、実施例３３に従って調整されたネブライザー用組成物を用いた。また、ネブライザー用組成物を投与した後の安全性を評価した。 When evaluating only the pharmacokinetics in plasma, the dosage is 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg as the active ingredient (indicating the weight as an anhydride. The same applies in Test Example 10 below). Administered. For the dosing, nebulizer compositions prepared according to Example 29, Example 30, Example 31, Example 32, and Example 33 were used. Moreover, the safety | security after administering the composition for nebulizers was evaluated.
　日本人健康成人男性を対象として、有効成分を含む組成物を、ネブライザーを用いて単回吸入投与したときの血漿中の活性代謝物の濃度は、最高血漿中濃度到達時間（Ｔｍａｘ、中央値）が４．０～６．０時間、消失半減期（Ｔ１/２、平均値）は５８．２９～１６５．８時間であった。血漿中の活性代謝物の最高血漿中濃度（Ｃｍａｘ）及び投与後の血漿中濃度下面積（ＡＵＣlast）は投与量にほぼ比例して増大した。有効成分量が、４０ｍｇ、８０ｍｇ、１６０ｍｇ、２４０ｍｇ、又は３２０ｍｇのネブライザー用組成物を単回投与したときの安全性について、バイタルサイン、誘導心電図の計測から、安全性上問題となる所見は認められなかった。 The concentration of active metabolite in plasma when a composition containing an active ingredient is administered by single inhalation using a nebulizer for Japanese healthy adult males is the maximum plasma concentration attainment time (Tmax, median) Was 4.0 to 6.0 hours, and the elimination half-life (T 1/2 , average value) was 58.29 to 165.8 hours. The maximum plasma concentration of active metabolite in plasma (Cmax) and the area under plasma concentration after administration (AUClast) increased approximately in proportion to the dose. Regarding the safety of a single administration of a nebulizer composition with an active ingredient amount of 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg, findings that pose a safety problem were observed from measurements of vital signs and induced electrocardiograms. There wasn't.
　肺胞内での薬物動態を評価する場合、投薬は、有効成分として１６０ｍｇを単回投与した。投薬には、実施例３１に従って調整されたネブライザー用組成物を用いた。 When evaluating the pharmacokinetics in the alveoli, 160 mg of the active ingredient was administered as a single dose. The nebulizer composition adjusted according to Example 31 was used for dosing.
　また、ネブライザー用組成物を投与した後の安全性を評価した。 Also, safety after administration of the nebulizer composition was evaluated.
　有効成分を単回吸入投与した後に、気管支肺胞洗浄（ｂｒｏｎｃｈｏａｌｖｅｏｌａｒ ｌａｖａｇｅ: ＢＡＬ）法を用いて肺胞内洗浄を行い、肺胞内洗浄液を回収し、肺胞粘液及び肺胞マクロファージ中の薬物濃度を測定した。肺胞粘液中の活性代謝物濃度は最初の測定時点（投与開始４時間後）に最高濃度を示した。その濃度は１４５９ ｎｇ/ｍＬであり、活性代謝物の分子量（３４６．３４）で換算すると約４．２μＭであった。投与開始１６８時間後の濃度は６３６．１ｎｇ／ｍＬ（約１．８μＭ）であった。 After a single inhalation administration of the active ingredient, intra-alveolar lavage is performed using the bronchoalveolar lavage (） BAL) method, the alveolar lavage fluid is collected, and the drug concentration in alveolar mucus and alveolar macrophages Was measured. The active metabolite concentration in alveolar mucus showed the highest concentration at the time of the first measurement (4 hours after the start of administration). The concentration was 1459 ng / mL, and it was about 4.2 μM in terms of the molecular weight of the active metabolite (346.34). The concentration after 168 hours from the start of administration was 636.1 ng / mL (about 1.8 μM).
　これらの値は、Ａ型及びＢ型インフルエンザウイルスのノイラミダーゼに対するＩＣ５０値［Ａ（Ｈ１Ｎ１）ｐｄｍ０９型：１．７０ｎＭ、Ａ（Ｈ３Ｎ２） 型：３．９８ｎＭ、Ｂ型： １４．８６ｎＭ］を十分に上回った（Ikematsu H, Kawai N, Iwaki N, et al. Clinical outcome of laninamivir octanoate hydrate for influenza in the 2013-2014 Japanese season. J Infect Chemother. 2015;21(11):802-7.）。 These values are sufficient for IC 50 values [A (H1N1) pdm09 type: 1.70 nM, A (H3N2) type: 3.98 nM, B type: 14.86 nM] for neuramidase of influenza A and B viruses. (Ikematsu H, Kawai N, Iwaki N, et al. Clinical outcome of laninamivir octanoate hydrate for influenza in the 2013-2014 Japanese season. J Infect Chemother. 2015; 21 (11): 802-7.).
　なお、日本人健康成人男性を対象とした、ネブライザー用組成物（有効成分１６０ｍｇ）を単回吸入投与した際の肺胞粘液中の活性代謝物の濃度は、報告されている吸入粉末剤（有効成分４０ｍｇ）を単回吸入投与した際の肺胞粘液中の活性代謝物の濃度と同程度であり、吸入粉末剤及びネブライザー用組成物とも有効成分を投与後、長時間にわたってＩＣ５０値を超える濃度が維持されていた（Antimicrobial Agents and Chemotherapy 2012, vol.56, No.7, p3873-3878）。 In addition, the concentration of active metabolites in alveolar mucus after a single inhalation administration of a nebulizer composition (active ingredient 160 mg) for Japanese healthy adult males is the reported inhaled powder (effective The concentration of the active metabolite in the alveolar mucus after a single inhalation administration of 40 mg of the component is over the IC 50 value over a long period of time after the administration of the active ingredient in both the inhalation powder and the nebulizer composition The concentration was maintained (Antimicrobial Agents and Chemotherapy 2012, vol.56, No.7, p3873-3878).
　以上の薬物動態の結果から、有効成分として４０～３２０ｍｇを、ネブライザーを用いて日本人健康成人男性に単回吸入投与したとき、活性代謝物の血漿中濃度は、投与量にほぼ比例して増加し、投与量の増加に伴った全身暴露が認められた。 Based on the above pharmacokinetic results, when a single inhalation dose of 40-320 mg as an active ingredient was administered to a Japanese healthy adult man using a nebulizer, the plasma concentration of the active metabolite increased in proportion to the dose. However, systemic exposure with increasing dose was observed.
　有効成分として１６０ｍｇを、ネブライザーを用いて日本人健康成人男性に単回投与したときの肺胞粘液中の活性代謝物は、投与後最初の評価時点（投与開始４時間後）でＡ型及びＢ型インフルエンザウイルスのノイラミダーゼに対するＩＣ５０値を十分上回る濃度が認められ、その濃度が長時間持続したので、持続的な薬効を発現する可能性が示された。 The active metabolite in alveolar mucus when a single dose of 160 mg as an active ingredient is administered to a Japanese healthy adult man using a nebulizer is the type A and B at the first evaluation time point (4 hours after the start of administration) after administration. Concentrations well above the IC 50 value for neuramidase of influenza A virus were observed, and the concentration lasted for a long time, indicating the possibility of developing sustained efficacy.
　すでに市販されているイナビル吸入粉末剤２０ｍｇの承認されている成人の投与量４０ｍｇについて、Ａ型及びＢ型インフルエンザウイルス感染症に対する治療・予防効果が確認されており、さらに、ネブライザー用組成物（有効成分１６０ｍｇ）単回投与時の肺胞粘膜中の薬物動態は、吸入粉末剤（有効成分４０ｍｇ）投与時の曝露を下回らないと考えられることから、ネブライザー用組成物（有効成分１６０ｍｇ）のＡ型及びＢ型インフルエンザウイルス感染症に対する治療・予防効果が期待できる。 An approved adult dose of 40 mg of inavir powder 20 mg already marketed has been confirmed to have therapeutic and prophylactic effects against influenza A and B influenza virus infections. Ingredient 160 mg) The pharmacokinetics in the alveolar mucosa at the time of single administration is considered not to be lower than the exposure at the time of administration of inhaled powder (active ingredient 40 mg). And a therapeutic / preventive effect on influenza B virus infection.
（試験例１１）健康成人男性対象のネブライザー用組成物と吸入粉末剤との薬物動態の比較試験
　日本人健康成人男性に、ネブライザー用組成物（有効成分量１６０ｍｇ、無水物としての重量を示す。）、及び、吸入粉末剤（有効成分量４０ｍｇ、無水物としての重量を示す。）を単回吸入投与したときの肺胞粘液中の薬物動態を比較した。ネブライザー用組成物は、実施例３１に従って調整されたネブライザー用組成物を用いた。吸入粉末剤は、市販のイナビル吸入粉末剤２０ｍｇを用いた。結果を表２１に示す。 (Test Example 11) Comparative test of pharmacokinetics between nebulizer composition and inhalation powder for healthy adult male subjects A composition for nebulizer (active ingredient amount 160 mg, weight as an anhydride is shown) to a Japanese healthy adult male. ), And pharmacokinetics in alveolar mucus after single inhalation administration of inhalable powder (active ingredient amount 40 mg, indicates weight as anhydride). As the nebulizer composition, the nebulizer composition prepared according to Example 31 was used. As the inhalation powder, 20 mg of a commercially available inavir inhalation powder was used. The results are shown in Table 21.
Figure JPOXMLDOC01-appb-T000023
 Ｃｍａｘ、ＡＵＣｉｎｆ、Ｔｍａｘ、及びＴ1/2 は推定値（標準誤差）を示す。
Figure JPOXMLDOC01-appb-T000023
 Cmax, AUCinf, Tmax, and T1 / 2 represent estimated values (standard errors).
　有効成分の活性代謝物の肺胞粘液中濃度について、最高血漿中濃度（Ｃｍａｘ）は吸入粉末剤投与の方が高値傾向を示したものの、最高血漿中濃度（Ｃｍａｘ）を示した時点以降はネブライザー用組成物が吸入粉末剤よりも高い傾向にあり、無限大時間までの血漿中濃度－時間曲線下面積（ＡＵＣｉｎｆ）はネブライザー用組成物の方が約２．８倍高値を示し、最高血漿中濃度到達時間（Ｔｍａｘ、中央値）及び消失半減期（Ｔ１/２、平均値）は、ネブライザー用組成物と吸入粉末剤とで差異は認められなかった。
ネブライザー用組成物及び吸入粉末剤を単回吸入投与した場合の活性代謝物の最高血漿中濃度（Ｃｍａｘ）及び無限大時間までの血漿中濃度－時間曲線下面積（ＡＵＣｉｎｆ）は、ネブライザー用組成物も吸入粉末剤も投与量にほぼ比例した増加を示した。 Regarding the alveolar mucus concentration of the active metabolite of the active ingredient, the maximum plasma concentration (Cmax) showed a higher tendency when administered by inhalation powder, but after the time when the maximum plasma concentration (Cmax) was shown, the nebulizer Composition tends to be higher than inhaled powder, and the area under the plasma concentration-time curve (AUCinf) up to infinity is about 2.8 times higher in the nebulizer composition, with the highest plasma Concentration arrival time (Tmax, median) and disappearance half-life (T1 / 2 , average value) were not different between the nebulizer composition and the inhaled powder.
The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUCinf) of the active metabolite when a nebulizer composition and an inhalation powder are administered by single inhalation are shown in the composition for nebulizer Both the inhalation powder and the inhalation powder showed an increase almost proportional to the dose.
　市販のイナビル吸入粉末剤２０ｍｇは、ラニナミビルオクタン酸エステル水和物を有効成分とする吸入粉末剤で、１０歳以上の小児と成人について承認された投与量である有効成分量４０ ｍｇ（無水物としての重量を示す）でインフルエンザウイルス感染症の治療・予防効果が確認されている。 Commercially available inavir powder 20 mg is an inhaler powder containing laninamivir octanoate hydrate as an active ingredient, and an active ingredient amount of 40 mg (anhydrous), which is an approved dose for children over 10 years of age and adults. (Indicating the weight as a product) has been confirmed to be effective in treating and preventing influenza virus infection.
　前述の試験例１０に示すように、有効成分８０ｍｇ、１６０ｍｇ、２４０ｍｇ、３２０ｍｇのネブライザー用組成物で安全性に問題がなかった。 As shown in Test Example 10 above, there were no safety problems with the nebulizer composition of active ingredients 80 mg, 160 mg, 240 mg, and 320 mg.
　これらのことを考慮すると、ネブライザー用組成物の有効成分量８０ｍｇ～３２０ｍｇでインフルエンザ治療・予防効果を示す可能性が示唆された。 Considering these facts, it was suggested that the effective amount of the active ingredient of the nebulizer composition may be 80 mg to 320 mg to show an influenza treatment / prevention effect.
（試験例１２）小児及び高齢者の喚気機能の検討試験
　成長過程にある小児や換気機能が低下している高齢者の、ネブライザー用組成物の用法用量を設定するために、小児及び高齢者を対象として、喚気機能を測定した。 (Experimental example 12) Examination of arousal function of children and the elderly In order to set the dosage of nebulizer composition for children in the process of growth and elderly people with poor ventilation function, The arousal function was measured as a target.
　健康な１歳以上１２歳以下の小児、７５歳以上の高齢者を対象とした。また、２０歳以上４０歳以下の成人を対照として加えた。結果を表２２に示す。 Targeted healthy children aged between 1 and 12 years old and elderly people aged 75 and over. Adults aged 20 to 40 were added as controls. The results are shown in Table 22.
Figure JPOXMLDOC01-appb-T000024
 平均値（最小値、最大値）
Figure JPOXMLDOC01-appb-T000024
 Average value (minimum value, maximum value)
　１歳～１２際の小児の一回換気量、１分間の換気量（分時換気量）は、年齢に伴い増加する傾向が見られた。この試験に参加した小児のうち、インフルエンザウイルス感染症を発症した者について、罹患時の換気量を測定し、正常時の換気量と比較したところ、大きな違いは認められなかった。結果を表２３に示す。 1) Tidal volume and 1 minute ventilation (minute ventilation) of children from 1 to 12 years tended to increase with age. Of the children who participated in this study, those who developed influenza virus infection were measured for ventilation at the time of illness, and compared with normal ventilation, there was no significant difference. The results are shown in Table 23.
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
　したがって、小児がインフルエンザウイルス感染症を発症した場合でも、極端に換気量が低下するような状況にはならないことが示唆された。 Therefore, it was suggested that even if a child develops an influenza virus infection, the situation does not cause an extremely low ventilation.
　市販のイナビル吸入粉末剤２０ｍｇについて、１０歳未満の小児に承認された投与量は、１０歳以上の小児と成人に承認された投与量である有効成分量４０ ｍｇ（無水物としての重量を示す）の半量である有効成分量２０ｍｇ（無水物としての重量を示す）でインフルエンザウイルス感染症の治療効果を示すことが確認されている。
試験例１０に示すように、成人では、ネブライザー用組成物（有効成分１６０ｍｇ）で吸入粉末剤（有効成分４０ｍｇ）のＡ型及びＢ型インフルエンザウイルス感染症に対する治療・予防効果が期待できる。
したがって、ネブライザー用組成物においても１０歳以上の小児および成人で有効性が期待される有効性分量１６０ｍｇの半量である有効成分量８０ｍｇで有効性を示す可能性が考えられる。 Regarding 20 mg of commercially available inavir powder, the dose approved for children under 10 years old is the amount of active ingredient approved for children over 10 years old and adults (indicating the weight as an anhydride) It is confirmed that a therapeutic effect of influenza virus infection is shown at an active ingredient amount of 20 mg (indicating the weight as an anhydride), which is half the amount of).
As shown in Test Example 10, in adults, the nebulizer composition (active ingredient 160 mg) can be expected to have a therapeutic / preventive effect on infectious diseases of type A and type B influenza virus inhalation powder (active ingredient 40 mg).
Therefore, there is a possibility that the nebulizer composition may be effective at an active ingredient amount of 80 mg, which is a half of an effective dose of 160 mg, which is expected to be effective in children and adults 10 years or older.
　また、試験例１０に示すように、日本人健康成人男性において、有効性分量３２０ｍｇまでの投与量で安全性上問題となる所見は認められなかったことから、１０歳未満の小児においても、有効成分量８０～３２０ｍｇで有効性が示されることが期待できる。 In addition, as shown in Test Example 10, in Japanese healthy adult males, no evidence of safety problems was observed at doses up to an effective dose of 320 mg. It can be expected that the effectiveness is shown at an ingredient amount of 80 to 320 mg.
　高齢者については、成人と比べて喚気機能に大きな違いは見られなかった。したがって、日本人健康成人男性について治療・予防効果が期待できるネブライザー用組成物（有効成分８０～３２０ｍｇ）について、高齢者についても治療・予防効果を示す可能性が示唆された。 For the elderly, there was no significant difference in the arousal function compared to adults. Therefore, it was suggested that the nebulizer composition (active ingredient 80 to 320 mg) that can be expected to have a therapeutic / preventive effect for Japanese healthy adult males may also have a therapeutic / preventive effect for the elderly.
（試験例１３）成人患者対象の治療効果の検討試験
　成人及び１０歳以上の小児のＡ型又はＢ型インフルエンザウイルス感染症患者を対象として、プラセボを対照薬とする単盲検比較試験として実施する。ネブライザー用組成物の有効成分量は１６０ｍｇとする。 (Test Example 13) Examination of therapeutic effect on adult patients Targeted in adults and children aged 10 years and older, who are type A or B influenza virus infection patients, this is a single-blind comparative study using placebo as a control drug. . The active ingredient amount of the nebulizer composition is 160 mg.
　治療用途の有効性は、インフルエンザ罹病時間、すなわち、投薬終了時刻から、インフルエンザ症状がすべてなくなる、又は軽度になり、それらが２１．５ 時間以上継続する最初の時点までの時間を主要な評価項目とする。 The effectiveness of the therapeutic use is defined as the time from the onset of influenza, that is, the time from the end of medication to the first point at which all influenza symptoms disappear or become mild, and last for 21.5 hours or longer. To do.
（試験例１４）小児患者対象の治療効果の検討試験
　１０歳未満のインフルエンザウイルス感染症患者を対象とした非対照非盲検試験を実施する。ネブライザー用組成物の有効成分量は１６０ ｍｇとする。 (Test Example 14) Examination of therapeutic effect on pediatric patient subjects An uncontrolled open-label study is conducted on patients with influenza virus infection younger than 10 years. The amount of the active ingredient in the nebulizer composition is 160 mg.
　治療用途の有効性は、インフルエンザ罹病時間、すなわち、投薬終了時刻から、インフルエンザ症状がすべてなくなる、又は軽度になり、それらが２１．５ 時間以上継続する最初の時点までの時間を主要な評価項目とする。
  The effectiveness of the therapeutic use is the primary endpoint of the time from influenza onset, i.e., the time from the end of medication to the first time that all influenza symptoms disappear or become mild and continue for 21.5 hours or more. To do.

Claims (34)


  1. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、さらに分散剤と浸透圧調節剤を含有するネブライザー用組成物。
    A composition for nebulizers containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersant and an osmotic pressure regulator.
  2. 　ラニナミビルオクタン酸エステル水和物を１～２０重量％含有する請求項１に記載のネブライザー用組成物。 The composition for a nebulizer according to claim 1, comprising 1 to 20% by weight of laninamivir octanoate hydrate.
  3. 　ラニナミビルオクタン酸エステル水和物を３～１０重量％含有する請求項１又は２に記載のネブライザー用組成物。 The nebulizer composition according to claim 1 or 2, which contains 3 to 10% by weight of laninamivir octanoate hydrate.
  4. 　ラニナミビルオクタン酸エステル水和物のレーザー回折散乱式粒度分布測定法における５０重量％の粒子径が５．０μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が１２．０μｍ以下である請求項１乃至３のいずれか１項に記載のネブライザー用組成物。 The particle size of 50% by weight in the laser diffraction / scattering particle size distribution measurement method of laninamivir octanoate hydrate is 5.0 μm or less, and the particle size of 90% by weight in the laser diffraction / scattering particle size distribution measurement method The composition for a nebulizer according to any one of claims 1 to 3, wherein is 12.0 µm or less.
  5. 　ラニナミビルオクタン酸エステル水和物のレーザー回折散乱式粒度分布測定法における５０重量％の粒子径が３．２μｍ以下であり、かつ、レーザー回折散乱式粒度分布測定法における９０重量％の粒子径が８．０μｍ以下である請求項１乃至３のいずれか１項に記載のネブライザー用組成物。 The particle size of 50% by weight in the laser diffraction scattering particle size distribution measurement method of laninamivir octanoate hydrate is 3.2 μm or less, and the particle size of 90% by weight in the laser diffraction scattering particle size distribution measurement method The composition for nebulizers of any one of Claims 1 thru | or 3 which are 8.0 micrometers or less.
  6. 　分散剤が、ポリソルベート、ソルビタンモノラウレート、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）及び、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）からなる群より選択される１種若しくは２種を組み合わせたものである、請求項１乃至５のいずれか１項に記載のネブライザー用組成物。 The dispersant is a combination of one or two selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). 6. The nebulizer composition according to any one of 5 above.
  7. 　分散剤がチロキサポールである、請求項１乃至５のいずれか１項に記載のネブライザー用組成物。 The composition for a nebulizer according to any one of claims 1 to 5, wherein the dispersant is tyloxapol.
  8. 　チロキサポールの含有率が、０．０１～１重量％である、請求項７に記載のネブライザー用組成物。 The nebulizer composition according to claim 7, wherein the content of tyloxapol is 0.01 to 1% by weight.
  9. 　チロキサポールの含有率が、０．０５～０．５重量％である、請求項７に記載のネブライザー用組成物。 The nebulizer composition according to claim 7, wherein the content of tyloxapol is 0.05 to 0.5% by weight.
  10. 　分散剤がポリオキシエチレンソルビタンモノラウレート及びソルビタンモノラウレートである、請求項１乃至５のいずれか１項に記載のネブライザー用組成物。 The composition for a nebulizer according to any one of claims 1 to 5, wherein the dispersant is polyoxyethylene sorbitan monolaurate or sorbitan monolaurate.
  11. 　ポリオキシエチレンソルビタンモノラウレートの含有率が０．０１～０．５重量％であり、ソルビタンモノラウレートの含有率が０．０１～０．５重量％である請求項１０に記載のネブライザー用組成物。 11. The nebulizer according to claim 10, wherein the content of polyoxyethylene sorbitan monolaurate is 0.01 to 0.5% by weight and the content of sorbitan monolaurate is 0.01 to 0.5% by weight. Composition.
  12. 　ポリオキシエチレンソルビタンモノラウレートの含有率が０．０３８～０．２重量％であり、ソルビタンモノラウレートの含有率が０．１～０．２重量％である請求項１０に記載のネブライザー用組成物。 The nebulizer according to claim 10, wherein the content of polyoxyethylene sorbitan monolaurate is 0.038 to 0.2 wt%, and the content of sorbitan monolaurate is 0.1 to 0.2 wt%. Composition.
  13. 　浸透圧調節剤が塩化ナトリウム又は乳糖水和物である、請求項１乃至１２のいずれか１項に記載のネブライザー用組成物。 The composition for a nebulizer according to any one of claims 1 to 12, wherein the osmotic pressure regulator is sodium chloride or lactose hydrate.
  14. 　浸透圧調節剤が塩化ナトリウムである、請求項１乃至１２のいずれか１項に記載のネブライザー用組成物、 The nebulizer composition according to any one of claims 1 to 12, wherein the osmotic pressure adjusting agent is sodium chloride.
  15. 　塩化ナトリウムの含有率が０．４５～１．８重量％である請求項１３又は１４に記載のネブライザー用組成物。 The composition for a nebulizer according to claim 13 or 14, wherein the sodium chloride content is 0.45 to 1.8% by weight.
  16. 　乳糖水和物の含有率が５～１０重量％である請求項１３に記載のネブライザー用組成物。 The nebulizer composition according to claim 13, wherein the content of lactose hydrate is 5 to 10% by weight.
  17. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、さらに分散剤を含有する凍結乾燥製剤。 A freeze-dried preparation containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient and further containing a dispersant.
  18. 　分散剤が、ポリソルベート、ソルビタンモノラウレート、チロキサポール、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）及び、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）からなる群から選択される１種若しくは２種を組み合わせたものである、請求項１７に記載の凍結乾燥製剤。 The dispersing agent is one or a combination of two selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol, hydroxypropylmethylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa). The lyophilized formulation described.
  19. 　分散剤がチロキサポールである請求項１７に記載の凍結乾燥製剤。 The lyophilized preparation according to claim 17, wherein the dispersing agent is tyloxapol.
  20. 　さらに浸透圧調節剤を含有する請求項１７乃至１９のいずれか１項に記載の凍結乾燥製剤。 The lyophilized preparation according to any one of claims 17 to 19, further comprising an osmotic pressure regulator.
  21. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩の含有率が、５５～９５重量％であり、分散剤の含有率が１～１０重量％であり、浸透圧調節剤の含有率が４～３５重量％である請求項２０に記載の凍結乾燥製剤。 The content of laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is 55 to 95% by weight, the content of the dispersant is 1 to 10% by weight, and the content of the osmotic pressure regulator The lyophilized preparation according to claim 20, wherein the ratio is 4 to 35% by weight.
  22. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩とチロキサポールからなる凍結乾燥製剤。 A lyophilized preparation comprising laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof and tyloxapol.
  23. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩の含有率が、９３．０～９８．５重量％であり、チロキサポールの含有率が１．５～７．０重量％である請求項２２に記載の凍結乾燥製剤。 The content of laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof is 93.0 to 98.5% by weight, and the content of tyloxapol is 1.5 to 7.0% by weight. The lyophilized preparation according to claim 22.
  24. 　請求項１乃至１６のいずれか１項に記載のネブライザー用組成物を、ネブライザーを用いて噴霧して吸入する方法。 A method of inhaling the nebulizer composition according to any one of claims 1 to 16 by spraying it using a nebulizer.
  25. 　請求項１７乃至２３のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、ネブライザーを用いて噴霧して吸入する方法。 A method of inhaling a lyophilized preparation according to any one of claims 17 to 23 by dispersing it in a suspending liquid to give an inhalation liquid and spraying it with a nebulizer.
  26. 　請求項１乃至１６のいずれか１項に記載のネブライザー用組成物からなるインフルエンザウイルス感染症の予防又は治療剤。 A prophylactic or therapeutic agent for influenza virus infection comprising the nebulizer composition according to any one of claims 1 to 16.
  27. 　請求項１７乃至２３のいずれか１項に記載の凍結乾燥製剤を懸濁用液にて分散して調製される吸入液剤からなるインフルエンザウイルス感染症の予防又は治療剤。 An agent for preventing or treating influenza virus infection comprising an inhalation solution prepared by dispersing the lyophilized preparation according to any one of claims 17 to 23 in a suspension solution.
  28. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して４０乃至３２０ｍｇである、請求項１乃至１６のいずれか１項に記載のネブライザー用組成物。 It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dose of the active ingredient is 40 to 320 mg in terms of anhydride per administration. Item 17. The nebulizer composition according to any one of Items 1 to 16.
  29. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して８０ｍｇである、請求項１乃至１６のいずれか１項に記載のネブライザー用組成物。 2. The lanamivir octanoic acid ester hydrate or a pharmacologically acceptable salt thereof is contained as an active ingredient, and the dose of the active ingredient is 80 mg in terms of anhydride per administration. The composition for nebulizers of any one of thru | or 16.
  30. 　ラニナミビルオクタン酸エステル水和物又はその薬理上許容される塩を有効成分として含有し、該有効成分の投与量が、１回の投与につき無水物に換算して１６０ｍｇである、請求項１乃至１６のいずれか１項に記載のネブライザー用組成物。 The lanamivir octoate hydrate or a pharmacologically acceptable salt thereof is contained as an active ingredient, and the dose of the active ingredient is 160 mg in terms of anhydride per administration. The composition for nebulizers of any one of thru | or 16.
  31. 　請求項１乃至１６、及び、請求項２８乃至３０のいずれか１項に記載のネブライザー用組成物を、インフルエンザウイルスの発症前のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の予防方法。 A nebulizer composition according to any one of claims 1 to 16 and claim 28 to 30, wherein the nebulizer composition is inhaled by being nebulized with a nebulizer into a human respiratory organ before the onset of influenza virus. How to prevent influenza virus infection.
  32. 　請求項１乃至１６、及び、請求項２８乃至３０のいずれか１項に記載のネブライザー用組成物を、インフルエンザウイルスの発症時のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザ感染症の治療方法。 The nebulizer composition according to any one of claims 1 to 16 and claim 28 to 30 is inhaled by being nebulized by using a nebulizer into a human respiratory organ at the onset of influenza virus. How to treat influenza infections.
  33. 　請求項１７乃至２３のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、インフルエンザウイルスの発症前のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の予防方法。 24. The freeze-dried preparation according to any one of claims 17 to 23 is dispersed in a suspension liquid to form an inhalation solution, and sprayed on a human respiratory tract before onset of influenza virus using a nebulizer. How to prevent influenza virus infection by inhalation.
  34. 　請求項１７乃至２３のいずれか１項に記載の凍結乾燥製剤を、懸濁用液にて分散して吸入液剤とし、インフルエンザウイルスの発症時のヒトの呼吸器に、ネブライザーを用いて噴霧して吸入することによるインフルエンザウイルス感染症の治療方法。 The freeze-dried preparation according to any one of claims 17 to 23 is dispersed in a suspension liquid to form an inhalation solution, which is sprayed onto a human respiratory organ at the onset of influenza virus using a nebulizer. A method for treating influenza virus infection by inhalation.
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