TWI762449B - Composition for nebulizer - Google Patents
Composition for nebulizer Download PDFInfo
- Publication number
- TWI762449B TWI762449B TW105124890A TW105124890A TWI762449B TW I762449 B TWI762449 B TW I762449B TW 105124890 A TW105124890 A TW 105124890A TW 105124890 A TW105124890 A TW 105124890A TW I762449 B TWI762449 B TW I762449B
- Authority
- TW
- Taiwan
- Prior art keywords
- composition
- weight
- nebulizer
- active ingredient
- freeze
- Prior art date
Links
Classifications
-
- 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
- A61K9/0012—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
- A61K9/14—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
Abstract
本發明之課題係提供一種有用於預防及/或治療流行性感冒病毒(influenza virus)感染症之噴霧器用組成物。 The subject of the present invention is to provide a composition for a nebulizer useful for the prevention and/or treatment of influenza virus (influenza virus) infection.
本發明之解決手段係一種噴霧器用組成物，其含有拉尼娜米韋辛酸酯(laninamivir octanoate)水合物或其藥理上可容許的鹽作為有效成分。 The solution of the present invention is a nebulizer composition containing laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient.
Description
本發明係關於一種流行性感冒病毒(influenza virus)感染症之治療或預防用之噴霧器用組成物，其以具有神經胺酸酶(neuraminidase)抑制活性的拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分。 The present invention relates to a composition for a nebulizer for the treatment or prevention of influenza virus (influenza virus) infection, comprising laninamivir octanoate hydrate having neuraminidase inhibitory activity or its pharmacological Tolerable salts are used as active ingredients.
拉尼娜米韋辛酸酯水合物顯示優異的神經胺酸酶抑制作用，藉由被投予至接受者之呼吸器官，並滯留於接受者之呼吸器官組織(上呼吸道、肺等)，而發揮流行性感冒病毒感染症之治療/預防效果(專利文獻1~3)。 La Nina mivir octanoate hydrate exhibits excellent neuraminidase inhibitory effect, and is prevalent by being administered to the recipient's respiratory organs and retained in the recipient's respiratory tissues (upper respiratory tract, lung, etc.). Therapeutic/preventive effects of influenza virus infection (Patent Documents 1 to 3).
拉尼娜米韋辛酸酯水合物因藉由使滯留於接受者之呼吸器官組織，而顯示抗流行性感冒作用，故拉尼娜米韋辛酸酯水合物以非經口路徑使到達呼吸器官組織的投予法及投予劑型係有必要的。因此，已揭露乾燥粉末吸入製劑作為將拉尼娜米韋辛酸酯水合物以非經口路徑投予的劑型(專利文獻4)。 La Nina mivir octanoate hydrate exhibits anti-influenza effect by being retained in the recipient's respiratory tissue, so latrine mivir octanoate hydrate is administered to the respiratory tissue through a non-oral route. Administration and dosage forms are necessary. Therefore, a dry powder inhalation preparation has been disclosed as a dosage form for parenteral administration of laninamivir octanoate hydrate (Patent Document 4).
乾燥粉末吸入製劑，具體而言，吸入用之粉末處方被收藏於膠囊、浮泡(blister)、裝置內之貯器、劑 量盤(dosing disc)等之容器，藉由接受者本身的吸氣而自裝置吸入1次投予量的粉末。然而，兒童、高齡者、呼吸功能低下的患者等之自發呼吸困難者，有未適當處理乾燥粉末吸入製劑，吸入充分量的藥物為困難的情形。又，自發呼吸困難者亦有難以確保充分量之吸氣的情形。對於此種自發呼吸困難者，正冀望使充分量之藥物安定而到達呼吸器官組織用之適合的投予法及投予劑型之開發。 Dry powder inhalation preparations, specifically, powder formulations for inhalation contained in capsules, blisters, receptacles in devices, doses In containers such as dosing discs, a single dose of powder is inhaled from the device by the recipient's own inhalation. However, in children, the elderly, and patients with low respiratory function who have spontaneous breathing difficulties, there are cases in which it is difficult to inhale a sufficient amount of the drug without properly handling the dry powder inhalation preparation. In addition, there are cases in which it is difficult to ensure a sufficient amount of inhalation for those with spontaneous breathing difficulties. For such spontaneous dyspnea, the development of a suitable administration method and administration dosage form for stabilizing a sufficient amount of the drug to reach the respiratory tissue is desired.
於耳鼻咽喉科領域，就即使兒童亦可確實地吸入的投予法而言，已知有利用噴霧器的投予法。又，於支氣管性氣喘或囊性纖維變性(cystic fibrosis)等之呼吸器官疾病之治療，即使於兒童或自發呼吸困難者，已亦實行利用噴霧器之投予作為可確實地吸入的投予法。如此，雖然噴霧器已廣泛用於兒童、高齡者、包含自發呼吸困難者的患者，但流行性感冒病毒感染症用之噴霧器用之組成物則迄今仍未上市。 In the field of otorhinolaryngology, an administration method using a nebulizer is known as an administration method that can be reliably inhaled even by children. In addition, in the treatment of respiratory diseases such as bronchial asthma and cystic fibrosis, even in children or those with spontaneous breathing difficulties, administration by a nebulizer has been performed as an administration method that can be reliably inhaled. In this way, although nebulizers have been widely used for children, the elderly, and patients including those with spontaneous breathing difficulties, compositions for nebulizers for influenza virus infection have not yet been marketed.
抗流行性感冒藥，尤其是作為胺酸酶抑制劑，已販售奥司他韋(Zanamivir)磷酸鹽(商標名克流感(Tamiflu)、專利文獻5)、扎那米韋(Zanamivir)水合物(商標名瑞樂沙(Relenza)、專利文獻6)及帕拉米韋(Peramivir)水合物(商標名瑞貝塔(Rapiacta)、專利文獻7)。 Anti-influenza drugs, especially as amino acid enzyme inhibitors, have been sold oseltamivir (Zanamivir) phosphate (trade name Tamiflu, Patent Document 5), zanamivir (Zanamivir) hydrate (trade name Relenza, Patent Document 6) and Peramivir hydrate (trade name Rapiacta, Patent Document 7).
克流感為經口投予製劑，作為膠囊劑或乾粉漿(dry syrup)製劑被販售。又，瑞貝塔為點滴靜注用之注射劑。此等之藥劑因投予路徑為非吸入，故選擇噴霧器作為投予手段係不可能的。 Grampus is a preparation for oral administration, and is sold as a capsule or a dry syrup preparation. In addition, Rebetta is an injection for intravenous infusion. Since the route of administration of these medicines is not inhalation, it is impossible to select a nebulizer as the means of administration.
扎那米韋(商標名瑞樂沙)雖為吸入用製劑，但有必要於複數日間連續投予。就沒有噴霧器的大部分患者而言，將瑞樂沙以噴霧器投予時，投予之時必須到醫院，故有對身體的負擔。 Although zanamivir (trade name Reloza) is a preparation for inhalation, it is necessary to continuously administer it over several days. For most patients who do not have a nebulizer, when Reloza is administered with a nebulizer, it is necessary to go to the hospital at the time of administration, which is a burden on the body.
正冀望以較少的投予次數完成治療的方式的神經胺酸酶抑制劑之噴霧器用製劑之開發。 The development of a neuraminidase inhibitor nebulizer formulation in which the treatment can be completed with a smaller number of administrations is expected.
[專利文獻1]日本專利第3209946號公報(美國專利第6340702號說明書、歐洲專利第823428號說明書) [Patent Document 1] Japanese Patent No. 3209946 (US Patent No. 6340702 specification, European Patent No. 823428 specification)
[專利文獻2]日本專利第3920041號公報(美國專利第6844363號說明書、歐洲專利第1277750號說明書) [Patent Document 2] Japanese Patent No. 3920041 (US Patent No. 6844363 specification, European Patent No. 1277750 specification)
[專利文獻3]日本專利第4205314號公報(國際公開第2001/080892號小冊 [Patent Document 3] Japanese Patent No. 4205314 (International Publication No. 2001/080892 Pamphlet)
[專利文獻4]日本專利第5697199號公報(國際公開第2010/074113號小冊) [Patent Document 4] Japanese Patent No. 5697199 (International Publication No. 2010/074113 Pamphlet)
[專利文獻5]國際公開第96/26933號小冊 [Patent Document 5] International Publication No. 96/26933 Pamphlet
[專利文獻6]國際公開第91/16320號小冊 [Patent Document 6] International Publication No. 91/16320 Pamphlet
[專利文獻7]日本專利第4102022號公報(美國專利第6503745號說明書、歐洲專利第1040094號說明書) [Patent Document 7] Japanese Patent No. 4102022 (US Patent No. 6503745 specification, European Patent No. 1040094 specification)
本發明者們針對治療/預防流行性感冒病毒感染症的藥劑進行多年的專心研討。其結果發現，將拉 尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，藉由組成之適當選擇、粒徑之適當調節，可作成能夠有效地到達接受者之呼吸器官組織(上呼吸道、肺等)(亦即，呼吸器官到達性優異)，再者，吸入時之刺激性降低、物理安定性亦優異之噴霧器用之吸入液劑，而完成本發明。 The inventors of the present invention have conducted intensive research for many years on agents for treating/preventing influenza virus infection. As a result, it was found that the pull Ninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, through proper selection of composition and proper adjustment of particle size, can be made into the respiratory organ tissues (upper respiratory tract, upper respiratory tract, upper respiratory tract, upper respiratory tract, etc.) of recipients effectively. The present invention has been completed as an inhalation liquid preparation for a nebulizer, which exhibits reduced irritation during inhalation and is also excellent in physical stability, etc.) (that is, excellent in reachability to respiratory organs).
本發明為：[1]一種噴霧器用組成物，其含有拉尼娜米韋辛酸酯(laninamivir octanoate)水合物或其藥理上可容許的鹽作為有效成分，且進一步含有分散劑與浸透壓調節劑；[2]如前述[1]所記載的噴霧器用組成物，其含有1~20重量%之拉尼娜米韋辛酸酯水合物；[3]如前述[1]或[2]所記載的噴霧器用組成物，其含有3~10重量%之拉尼娜米韋辛酸酯水合物；[4]如前述[1]至[3]中任一項所記載的噴霧器用組成物，其中拉尼娜米韋辛酸酯水合物之雷射繞射散射式粒度分布測定法中的50重量%的粒徑為5.0μm以下，且雷射繞射散射式粒度分布測定法中的90重量%的粒徑為12.0μm以下；[5]如前述[1]至[3]中任一項所記載的噴霧器用組成物，其中拉尼娜米韋辛酸酯水合物之雷射繞射散射式粒度分布測定法中的50重量%的粒徑為3.2μm以下，且雷射繞射散射式粒度分布測定法中的90重量%的粒徑為8.0μm以下； [6]如前述[1]至[5]中任一項所記載的噴霧器用組成物，其中分散劑係組合選自包含聚山梨醇酯、山梨醇酐單月桂酸酯、泰洛沙泊(tyloxapol)、羥基丙基甲基纖維素(HPMC)及羧基甲基纖維素鈉(CMCNa)的群組中的1種或2種者；[7]如前述[1]至[5]中任一項所記載的噴霧器用組成物，其中分散劑為泰洛沙泊；[8]如前述[7]所記載的噴霧器用組成物，其中泰洛沙泊之含有率為0.01~1重量%；[9]如前述[7]所記載的噴霧器用組成物，其中泰洛沙泊之含有率為0.05~0.5重量%；[10]如前述[1]至[5]中任一項所記載的噴霧器用組成物，其中分散劑為聚氧乙烯山梨醇酐單月桂酸酯(polyoxyethylene sorbitan monolaurate)及山梨醇酐單月桂酸酯；[11]如前述[10]所記載的噴霧器用組成物，其中聚氧乙烯山梨醇酐單月桂酸酯之含有率為0.01~0.5重量%，山梨醇酐單月桂酸酯之含有率為0.01~0.5重量%；[12]如前述[12]所記載的噴霧器用組成物，其中聚氧乙烯山梨醇酐單月桂酸酯之含有率為0.038~0.2重量%，山梨醇酐單月桂酸酯之含有率為0.1~0.2重量%；[13]如前述[1]至[12]中任一項所記載的噴霧器用組成物，其中浸透壓調節劑為氯化鈉或乳糖水合物；[14]如前述[1]至[12]中任一項所記載的噴霧器用組成物，其中浸透壓調節劑為氯化鈉； [15]如前述[13]或[14]中任一項所記載的噴霧器用組成物，其中氯化鈉之含有率為0.45~1.8重量%；[16]如前述[13]所記載的噴霧器用組成物，其中乳糖水合物之含有率為5~10重量%；[17]一種冷凍乾燥製劑，其含有拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，且進一步含有分散劑；[18]如前述[17]所記載的冷凍乾燥製劑，其中分散劑為組合選自包含聚山梨醇酯、山梨醇酐單月桂酸酯、泰洛沙泊、羥基丙基甲基纖維素(HPMC)及羧基甲基纖維素鈉(CMCNa)的群組中的1種或2種者；[19]如前述[17]所記載的冷凍乾燥製劑，其中分散劑為泰洛沙泊；[20]如前述[17]至[19]中任一項之冷凍乾燥製劑，其進一步含有浸透壓調節劑；[21]如前述[20]所記載的冷凍乾燥製劑，其中拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽之含有率為55~95重量%，分散劑之含有率為1~10重量%，浸透壓調節劑之含有率為4~35重量%；[22]一種冷凍乾燥製劑，其係由拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽及泰洛沙泊所構成；[23]如前述[22]所記載的冷凍乾燥製劑，其中拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽之含有率為93.0~98.5重量%，泰洛沙泊之含有率為1.5~7.0重量%；[24]一種方法，其係使用噴霧器將如前述[1]至[16] 中任一項之噴霧器用組成物作噴霧而吸入的方法；[25]一種方法，其係將如前述[17]至[23]中任一項之冷凍乾燥製劑以懸浮用液加以分散而作成吸入液劑，並使用噴霧器作噴霧而吸入的方法；[26]一種流行性感冒病毒感染症之預防或治療劑，其係由如前述[1]至[16]中任一項之噴霧器用組成物所構成；[27]一種流行性感冒病毒感染症之預防或治療劑，其係由將如前述[17]至[23]中任一項之冷凍乾燥製劑以懸浮用液加以分散而被調製的吸入液劑所構成；[28]如前述[1]至[16]中任一項所記載的噴霧器用組成物，其含有拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，該有效成分之投予量就每1次之投予換算為無水物係40至320mg；[29]如前述[1]至[16]中任一項所記載的噴霧器用組成物，其含有拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，該有效成分之投予量就每1次之投予換算為無水物係80mg；[30]如前述[1]至[16]中任一項所記載的噴霧器用組成物，其含有拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，該有效成分之投予量就每1次之投予換算為無水物係160mg；[31]一種流行性感冒病毒感染症之預防方法，其係藉由將如前述[1]至[16]及前述[28]至[30]中任一項之噴霧器用組成物，對流行性感冒病毒之發病前的人類呼吸 器官，使用噴霧器加以噴霧而吸入；[32]一種流行性感冒病毒感染症之治療方法，其係藉由將如前述[1]至[16]及前述[28]至[30]中任一項之噴霧器用組成物，對流行性感冒病毒之發病時的人類呼吸器官，使用噴霧器加以噴霧而吸入；[33]一種流行性感冒病毒感染症之預防方法，其係藉由將如前述[17]至[23]中任一項之冷凍乾燥製劑，以懸浮用液加以分散而作成吸入液劑，對流行性感冒病毒之發病前之人類呼吸器官，使用噴霧器加以噴霧而吸入；及[34]一種流行性感冒病毒感染症之治療方法，其係藉由將如前述[17]至[23]中任一項之冷凍乾燥製劑，以懸浮用液加以分散而作成吸入液劑，對流行性感冒病毒之發病時之人類呼吸器官，使用噴霧器加以噴霧而吸入。 The present invention is: [1] a composition for a nebulizer, which contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further contains a dispersant and an osmotic pressure regulator; [2] The composition for a nebulizer according to the above [1], which contains 1 to 20% by weight of La Nina mivir octanoate hydrate; [3] The composition for a nebulizer according to the above [1] or [2] A composition containing 3 to 10% by weight of La Nina mivir octanoate hydrate; [4] the composition for a nebulizer according to any one of the aforementioned [1] to [3], wherein La Nina mivir octanoic acid The particle size of 50% by weight in the laser diffraction scattering particle size distribution measurement method of the ester 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 is 12.0 μm or less [5] The composition for a nebulizer according to any one of the aforementioned [1] to [3], wherein 50% by weight in the laser diffraction scattering particle size distribution measurement method of La Nina mivir octanoate hydrate The particle size is 3.2 μm or less, and the particle size of 90% by weight in the laser diffraction scattering particle size distribution measurement method is 8.0 μm or less; [6] The composition for a nebulizer according to any one of the aforementioned [1] to [5], wherein the dispersant-based combination is selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol ( tyloxapol), hydroxypropyl methylcellulose (HPMC) and 1 or 2 kinds of the group of carboxymethyl cellulose sodium (CMCNa); [7] as any one of the aforementioned [1] to [5] The composition for a nebulizer described in item, wherein the dispersant is tyloxapol; [8] the composition for a nebulizer as described in the aforementioned [7], wherein the content of tyloxapol is 0.01 to 1% by weight; [ 9] The composition for a nebulizer according to the above [7], wherein the content of tyloxapol is 0.05 to 0.5% by weight; [10] The nebulizer according to any one of the above [1] to [5] composition, wherein the dispersing agent is polyoxyethylene sorbitan monolaurate (polyoxyethylene sorbitan monolaurate) and sorbitan monolaurate; [11] The composition for a sprayer as described in the aforementioned [10], wherein the polymer The content rate of oxyethylene sorbitan monolaurate is 0.01 to 0.5% by weight, and the content rate of sorbitan monolaurate is 0.01 to 0.5% by weight; [12] The composition for sprayers described in the aforementioned [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; [13] As mentioned above [1] to [ 12] The composition for a nebulizer according to any one of the above, wherein the osmotic pressure regulator is sodium chloride or lactose hydrate; [14] The composition for a nebulizer according to any one of the above [1] to [12] material, wherein the osmotic pressure regulator is sodium chloride; [15] The composition for a nebulizer according to any one of the above [13] or [14], wherein the sodium chloride content is 0.45 to 1.8% by weight; [16] The nebulizer according to the above [13] Use composition, wherein the content rate of lactose hydrate is 5 to 10% by weight; [17] a freeze-dried preparation, which contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and further containing a dispersing agent; [18] the freeze-dried preparation according to the aforementioned [17], wherein the dispersing agent is a combination selected from the group consisting of polysorbate, sorbitan monolaurate, tyloxapol, hydroxypropylmethyl One or two of the group consisting of cellulose (HPMC) and sodium carboxymethylcellulose (CMCNa); [19] The freeze-dried preparation according to the aforementioned [17], wherein the dispersant is tyloxapol [20] The freeze-dried preparation according to any one of the aforementioned [17] to [19], which further contains an osmotic pressure regulator; [21] The freeze-dried preparation according to the aforementioned [20], wherein La Nina mivircin The content of the acid ester hydrate or its pharmacologically acceptable salt 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 is 4 to 35% by weight; [22 ] A freeze-dried preparation comprising La Nina mivir octanoate hydrate or a pharmacologically acceptable salt thereof and tyloxapol; [23] The freeze-dried preparation according to the aforementioned [22], wherein La Nina The content of mivir 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; [24] A method of applying a sprayer to As mentioned above [1] to [16] A method for inhaling the composition for a nebulizer by spraying according to any one of the above; [25] A method comprising dispersing the freeze-dried preparation according to any one of the aforementioned [17] to [23] with a suspension liquid to prepare A method of inhaling a liquid preparation and using a nebulizer for spraying and inhaling; [26] A preventive or therapeutic agent for influenza virus infection, which is composed of the nebulizer according to any one of the aforementioned [1] to [16] [27] A preventive or therapeutic agent for influenza virus infection, which is prepared by dispersing the freeze-dried preparation according to any one of the aforementioned [17] to [23] in a suspension liquid [28] The composition for a nebulizer according to any one of the aforementioned [1] to [16], which contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as The active ingredient, the dosage of the active ingredient is 40 to 320 mg of the anhydrous system per administration; [29] The composition for a nebulizer according to any one of the aforementioned [1] to [16], It contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dosage of the active ingredient is 80 mg of anhydrous per administration; [30] As mentioned above [1 ] The composition for nebulizer described in any one of [16], which contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, and the dosage of the active ingredient is 1 time The administration is converted to 160 mg of anhydrous; [31] A method for preventing influenza virus infection by adding any one of the aforementioned [1] to [16] and the aforementioned [28] to [30] Composition for nebulizer of item, for human respiration before the onset of influenza virus Organs, which are sprayed with a nebulizer and inhaled; [32] A method for treating influenza virus infection by adding any one of the aforementioned [1] to [16] and the aforementioned [28] to [30] The composition for nebulizer of the invention is used to spray and inhale the human respiratory organs during the onset of influenza virus by using a nebulizer; [33] A method for preventing influenza virus infection, which is achieved by mixing the above-mentioned [17] The freeze-dried preparation according to any one of [23], which is dispersed with a suspending liquid to make an inhalation liquid preparation, and the human respiratory organs before the onset of influenza virus are sprayed and inhaled using a nebulizer; and [34] a A method for treating influenza virus infection by dispersing the freeze-dried preparation according to any one of the aforementioned [17] to [23] with a suspension liquid to prepare an inhalation solution, which is effective against influenza virus The human respiratory organs at the time of the onset are sprayed with a nebulizer and inhaled.
本發明之噴霧器用組成物之有效成分為拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽。拉尼娜米韋辛酸酯水合物係下述式(I)與(II)所示之(I)：(2R,3R,4S)-3-乙醯胺-4-胍基-2-[(1R,2R)-2-羥基-1-甲氧基-3-(辛醯氧基)丙基]-3,4-二氫-2H-哌喃-6-甲酸一水合物與(II)：(2R,3R,4S)-3-乙醯胺-4-胍基-2-[(1S,2R)-3-羥基-1-甲氧基-2-(辛醯氧基)丙基]-3,4-二氫-2H-哌喃-6-甲酸一水合物的混合物。 The active ingredient of the composition for a nebulizer of the present invention is laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof. La Nina Mivir octanoate hydrate is (I) represented by the following formulas (I) and (II): (2R,3R,4S)-3-acetamide-4-guanidino-2-[(1R ,2R)-2-Hydroxy-1-methoxy-3-(octanoyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate with (II):( 2R,3R,4S)-3-acetamide-4-guanidino-2-[(1S,2R)-3-hydroxy-1-methoxy-2-(octanyloxy)propyl]-3 , 4-Dihydro-2H-pyran-6-carboxylic acid monohydrate mixture.
上述式(I)及(II)所示的拉尼娜米韋辛酸酯水合物因於分子內具有胍基及羧基，故可與藥理上未顯示毒性的酸或鹼結合而形成藥理上可容許的鹽。拉尼娜米韋辛酸酯水合物之「其藥理上可容許的鹽」係指此種鹽。 Since the laninamivir octanoate hydrate represented by the above formulas (I) and (II) has a guanidine group and a carboxyl group in the molecule, it can be combined with a pharmacologically non-toxic acid or base to form a pharmacologically acceptable. Salt. The "pharmacologically acceptable salt thereof" of La Nina mivir octanoate hydrate refers to such a salt.
就「藥理上可容許的鹽」而言，可列舉例如氫氟酸鹽、氫氯酸鹽、氫溴酸鹽、氫碘酸鹽之類的氫鹵酸鹽；硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽之類的無機酸鹽；甲烷磺酸鹽、乙烷磺酸鹽、三氟甲烷磺酸鹽之類的烷烴磺酸鹽；苯磺酸鹽、對甲苯磺酸鹽之類的芳基磺酸鹽；乙酸鹽、三氟乙酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽之類的有機酸鹽；甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之類的胺基酸鹽；鋰鹽、鈉鹽、鉀鹽之類的鹼金屬鹽；鈣鹽、鎂鹽之類的鹼土類金屬鹽；鋁鹽、鐵鹽、鋅鹽、銅鹽、鎳鹽、鈷鹽之類的金屬鹽；銨鹽、三級辛基胺鹽、二苯甲基胺鹽、
拉尼娜米韋辛酸酯水合物及其藥理上可容許的鹽有因放置於大氣中或與水混合會吸收水而形成水合物的情形。拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽之水合物係指此種水合物。 La ninamivir octanoate hydrate and pharmacologically acceptable salts thereof may absorb water when placed in the atmosphere or mixed with water to form a hydrate. La Nina mivir octanoate hydrate or a hydrate of a pharmacologically acceptable salt thereof refers to such a hydrate.
拉尼娜米韋辛酸酯水合物及其藥理上可容許的鹽係於分子內具有不對稱碳，而有立體異構物(包含鏡像異構物及非鏡像異構物)存在。此等之立體異構物及該等之任意比例之混合物(包含外消旋體)係被包含於本發明的有效成分之拉尼娜米韋辛酸酯水合物及其藥理上可容許的鹽。 La ninamivir octanoate hydrate and its pharmacologically acceptable salts have asymmetric carbons in the molecule, and stereoisomers (including enantiomers and non-spiroisomers) exist. These stereoisomers and mixtures (including racemates) of these in any ratio are included in the active ingredient of the present invention La Nina Mivir octanoate hydrate and pharmacologically acceptable salts thereof.
已知上述式(I)所表示的(2R,3R,4S)-3-乙醯胺-4-胍基-2-[(1R,2R)-2-羥基-1-甲氧基-3-(辛醯氧基)丙基]-3,4-二氫-2H-哌喃-6-甲酸一水合物被投予至溫血動物時，側鏈之第3位的醯氧基藉由水解等之代謝反應而變換為羥基，生成的化合物(III)：
顯示藥理活性(專利文獻1等)。又，上述式(II)所表示的(2R,3R,4S)-3-乙醯胺-4-胍基-2-[(1S,2R)-3-羥基-1- 甲氧基-2-(辛醯氧基)丙基]-3,4-二氫-2H-哌喃-6-甲酸一水合物被投予至溫血動物時，側鏈之第2位之醯氧基藉由水解等之代謝反應而被變換為羥基，同樣地有化合物(III)生成。於溫血動物之活體內，化合物(I)及化合物(II)任一者可被變換為活性代謝物的相同化合物(III)。 Shows pharmacological activity (Patent Document 1, etc.). Moreover, (2R,3R,4S)-3-acetamide-4-guanidino-2-[(1S,2R)-3-hydroxy-1- represented by the above formula (II) When methoxy-2-(octanoyloxy)propyl]-3,4-dihydro-2H-pyran-6-carboxylic acid monohydrate is administered to warm-blooded animals, the 2nd position of the side chain The acyloxy group is converted into a hydroxyl group by a metabolic reaction such as hydrolysis, and the compound (III) is produced in the same manner. In vivo in a warm-blooded animal, either compound (I) or compound (II) can be converted into the same compound (III) as the active metabolite.
本發明之噴霧器用組成物所含有的拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽之粒徑，較佳為雷射繞射散射式粒度分布測定法中的50重量%的粒徑為5.0μm以下，且雷射繞射散射式粒度分布測定法中的90重量%的粒徑為12.0μm以下，更佳為雷射繞射散射式粒度分布測定法中的50重量%的粒徑為3.2μm以下，且雷射繞射散射式粒度分布測定法中的90重量%的粒徑為8.0μm以下。 The particle size of the laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof contained in the composition for a nebulizer of the present invention is preferably 50% by weight of particles in the laser diffraction scattering particle size distribution measurement method. The diameter is 5.0 μm or less, and 90% by weight of the particle size in the laser diffraction scattering particle size distribution measurement method is 12.0 μm or less, more preferably 50 weight % in the laser diffraction scattering particle size distribution measurement method. The diameter is 3.2 μm or less, and the particle size of 90% by weight in the laser diffraction scattering particle size distribution measurement method is 8.0 μm or less.
為此範圍時，本發明之有效成分係尤其於吸入性優異，具有高的呼吸器官到達性而可通過咽頭到達至肺深部，其結果，發揮高且歷經長期的抗流行性感冒活性。 Within this range, the active ingredient of the present invention is particularly excellent in inhalation properties, has high respiratory organ reachability, and can reach deep lungs through the pharynx, and as a result, exhibits high anti-influenza activity over a long period of time.
本發明之噴霧器用組成物係除了上述有效成分之外，進一步含有分散劑與浸透壓調節劑的噴霧器用之吸入液劑。 The composition for a nebulizer of the present invention is an inhalation liquid preparation for a nebulizer which further contains a dispersant and an osmotic pressure regulator in addition to the above-mentioned active ingredients.
於本發明，分散劑係指於噴霧器用組成物中，用以使所含有的化合物，尤其是使有效成分於液中均勻地分散而被添加的化合物。就分散劑而言，可使用界面活性劑、或乳化劑。 In this invention, a dispersing agent means the compound which is added in order to make the compound contained in the composition for nebulizers, especially an active ingredient, uniformly disperse|distribute in a liquid. As the dispersing agent, a surfactant, or an emulsifier can be used.
作為分散劑，更具體而言，可例示組合選自 包含例如聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)、聚氧乙烯山梨醇酐單硬脂酸酯(Tween 60)、聚氧乙烯山梨醇酐參硬脂酸酯(Tween 65)、或聚氧乙烯山梨醇酐單油酸酯(Tween 80)之聚山梨醇酯、山梨醇酐單月桂酸酯(Span 20)、泰洛沙泊、羥基丙基甲基纖維素(HPMC)、及羧基甲基纖維素鈉(CMCNa)的群組中的1種或2種者。 As a dispersant, more specifically, a combination of selected from Contains, for example, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan stearate (Tween 65), or Polysorbate of polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monolaurate (Span 20), tyloxapol, hydroxypropyl methylcellulose (HPMC), and carboxyl One or two of the group of methylcellulose sodium (CMCNa).
此等之中，較佳為聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)、山梨醇酐單月桂酸酯(Span 20)、泰洛沙泊、羥基丙基甲基纖維素(HPMC)。聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)與山梨醇酐單月桂酸酯(Span 20)亦可組合而使用。 Among these, polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (Span 20), tyloxapol, hydroxypropyl methylcellulose (HPMC) are preferred . Polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (Span 20) can also be used in combination.
此等之中尤其更佳為泰洛沙泊，或組合聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)與山梨醇酐單月桂酸酯(Span 20)之2種者。 Among these, tyloxapol or a combination of two types of polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (Span 20) are particularly preferred.
此等之中尤其進一步較佳為泰洛沙泊。 Among these, tyloxapol is further preferred.
本發明之噴霧器用組成物含有浸透壓調節劑。 The composition for a sprayer of the present invention contains an osmotic pressure regulator.
於本發明，浸透壓調節劑係指用以調節本發明之噴霧器用組成物之浸透壓而被添加的化合物，藉由選擇使用作為浸透壓調節劑的化合物，可使本發明之噴霧器用組成物之浸透壓與體液之浸透壓相等，具體而言，與口腔內、呼吸器官組織(上呼吸道、肺等)的體液之浸透壓相等。藉由將本發明之噴霧器用組成物作成與體液等張，可降低本發明之噴霧器用組成物之吸入時的刺激，且可使能夠到達呼吸器官組織的本發明之有效成分量(微粒子量、FPD)增加。 In the present invention, the osmotic pressure regulator refers to a compound added to adjust the osmotic pressure of the composition for a nebulizer of the present invention. By selecting and using the compound as the osmotic pressure regulator, the composition for a nebulizer of the present invention can be obtained. The osmotic pressure is equal to the osmotic pressure of bodily fluids, specifically, the osmotic pressure of bodily fluids in the oral cavity and respiratory organ tissues (upper respiratory tract, lungs, etc.). By making the composition for a nebulizer of the present invention isotonic with body fluids, the irritation at the time of inhalation of the composition for a nebulizer of the present invention can be reduced, and the amount of the active ingredient of the present invention (amount of fine particles, FPD) increased.
就浸透壓調節劑而言，可列舉氯化鈉或乳糖水合物。 As the osmotic pressure regulator, sodium chloride or lactose hydrate can be exemplified.
此等中尤以氯化鈉為較佳。就氯化鈉之水溶液而言，可使用生理食鹽水。 Of these, sodium chloride is particularly preferred. As the aqueous solution of sodium chloride, physiological saline can be used.
以噴霧器吸入之際，每1次之本發明之噴霧器用組成物的容量，較佳為2~8ml，特佳為2ml。 When inhaling with a nebulizer, the volume of the composition for a nebulizer of the present invention per one time is preferably 2 to 8 ml, particularly preferably 2 ml.
於本發明之噴霧器用組成物，有效成分之含有率，較佳為1~20重量%，更佳為3~10重量%。為此範圍時，可對吸入本發明之噴霧器用組成物的接受者之呼吸器官組織(上呼吸道、肺等)，提供充分量的有效成分。 In the composition for a sprayer 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 organ tissue (upper respiratory tract, lung, etc.) of the recipient who inhales the composition for a nebulizer of the present invention.
於本發明之噴霧器用組成物，分散劑之含有率係依所使用的化合物而異，例如，使用泰洛沙泊的情形，含有率係較佳為0.01~1重量%，更佳為0.05~0.5重量%。 In the composition for a sprayer of the present invention, the content rate of the dispersant varies depending on the compound used. For example, in the case of using tyloxapol, the content rate is preferably 0.01 to 1% by weight, more preferably 0.05 to 0.05% by weight. 0.5% by weight.
使用羥基丙基甲基纖維素(HPMC)作為分散劑的情形，含有率係較佳為0.1~1重量%。 When using hydroxypropyl methylcellulose (HPMC) as a dispersant, the content rate is preferably 0.1 to 1% by weight.
使用聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)作為分散劑的情形，含有率係0.1~0.5重量%，較佳為0.138~0.4重量%。 When using polyoxyethylene sorbitan monolaurate (Tween 20) as a dispersant, the content rate is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
使用山梨醇酐單月桂酸酯(Span 20)作為分散劑的情形，含有率係0.1~0.5重量%，較佳為0.138~0.4重量%。 When using sorbitan monolaurate (Span 20) as a dispersant, the content rate is 0.1 to 0.5% by weight, preferably 0.138 to 0.4% by weight.
亦可合併使用聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)與山梨醇酐單月桂酸酯(Span 20)作為分散劑。合併使用聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)與 山梨醇酐單月桂酸酯(Span 20)的情形，含有率係較佳為，聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)為0.038~0.2重量%，山梨醇酐單月桂酸酯(Span 20)為0.1~0.2重量%。 It is also possible to use a combination of polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (Span 20) as dispersants. Combined use of polyoxyethylene sorbitan monolaurate (Tween 20) with In the case of sorbitan monolaurate (Span 20), the content of polyoxyethylene sorbitan monolaurate (Tween 20) is preferably 0.038 to 0.2% by weight, and sorbitan monolaurate ( Span 20) is 0.1 to 0.2% by weight.
為此範圍時，則於本發明之噴霧器用組成物中，顯示有效成分為優異的分散性。 Within this range, the composition for a nebulizer of the present invention exhibits excellent dispersibility of the active ingredient.
於本發明之噴霧器用組成物，浸透壓調節劑之含有率係依使用的化合物而異。例如，使用氯化鈉作為浸透壓調節劑的情形，本發明之噴霧器組成物中，氯化鈉係較佳為0.45~1.8重量%，使用乳糖水合物的情形，乳糖水合物係較佳為5~10重量%。 In the composition for a sprayer of the present invention, the content of the osmotic pressure regulator varies depending on the compound to be used. For example, in the case of using sodium chloride as the osmotic pressure regulator, in the spray composition of the present invention, the sodium chloride content is preferably 0.45 to 1.8% by weight, and in the case of using lactose hydrate, the lactose hydrate content is preferably 5% ~10 wt%.
本發明之冷凍乾燥製劑係含有拉尼娜米韋辛酸酯水合物或其藥理上可容許的鹽作為有效成分，進一步含有分散劑、或進一步含有浸透壓調節劑。藉由將本發明之冷凍乾燥製劑以懸浮用液加以分散，可獲得本發明之噴霧器用組成物。 The freeze-dried preparation of the present invention contains laninamivir octanoate hydrate or a pharmacologically acceptable salt thereof as an active ingredient, further contains a dispersing agent, or further contains an osmotic pressure regulator. The composition for a nebulizer of the present invention can be obtained by dispersing the freeze-dried preparation of the present invention as a liquid for suspension.
本發明之冷凍乾燥製劑所含有的分散劑係與本發明之噴霧器用組成物中所含有的分散劑相同。 The dispersant contained in the freeze-dried preparation of the present invention is the same as the dispersant contained in the composition for a nebulizer of the present invention.
能於本發明之冷凍乾燥製劑中含有的浸透壓調節劑亦與本發明之噴霧器用組成物中所含有的浸透壓調節劑相同。 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 composition for a nebulizer of the present invention.
本發明之冷凍乾燥製劑於包含有效成分、分散劑、及浸透壓調節劑的情形，於冷凍乾燥製劑所含有的有效成分之含有率係55~95重量%，分散劑之含有率係1.0~10.0重量%，浸透壓調節劑之含有率係4~35重量%。 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 in the freeze-dried preparation is 55 to 95% by weight, and the content of the dispersant is 1.0 to 10.0 % by weight, and the content of the osmotic pressure regulator is 4 to 35% by weight.
於本發明之冷凍乾燥製劑，亦可併用2種作為分散劑。例如，併用聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)及山梨醇酐單月桂酸酯(Span 20)作為分散劑，並使用氯化鈉作為浸透壓調節劑的情形，冷凍乾燥製劑中所含有的有效成分之含有率係60~90重量%，聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)之含有率係0.5~5.0重量%，山梨醇酐單月桂酸酯(Span 20)之含有率係1.5~5.0重量%，氯化鈉之含有率係8.0~30重量%為較佳。 In the freeze-dried preparation of the present invention, two types of dispersants may be used in combination. For example, when polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (Span 20) are used together as a dispersant, and sodium chloride is used as a osmotic pressure regulator, the freeze-dried preparation The content of the active ingredients contained 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 content rate is 1.5 to 5.0% by weight, and the content rate of sodium chloride is preferably 8.0 to 30% by weight.
本發明之冷凍乾燥製劑亦可為僅包含有效成分、及為分散劑的泰洛沙泊。於此種冷凍乾燥製劑中，冷凍乾燥製劑所含有的有效成分之含有率係93.0~98.5重量%，分散劑之含有率係1.5~7.0重量%。 The freeze-dried preparation of the present invention may be tyloxapol containing only an active ingredient and 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.
藉由本發明之冷凍乾燥製劑所調製的本發明之噴霧器用組成物，可使用噴霧器，較佳為噴射式噴霧器(亦稱為壓縮機式噴霧器)，而被投予至接受者。 The composition for a nebulizer of the present invention prepared from the freeze-dried preparation of the present invention can be administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
本發明之噴霧器用組成物因於組成物中之有效成分的分散性優異，故即使為兒童或高齡者、呼吸功能降低的人之所謂的自發呼吸困難的接受者，有效成分可效率佳地到達至接受者之呼吸器官組織(上呼吸道、肺等)。 The composition for a nebulizer of the present invention is excellent in the dispersibility of the active ingredient in the composition, so that the active ingredient can efficiently reach the recipients of so-called spontaneous dyspnea such as children, the elderly, and persons with reduced respiratory function. To the recipient's respiratory organs (upper respiratory tract, lungs, etc.).
於有效成分為具有特定之粒徑分布的本發明之噴霧器用組成物中，有效成分可到達至接受者之呼吸器官組織，尤其是到達上呼吸道或肺，據此，維持高且歷經長期的抗流行性感冒活性。 In the composition for a nebulizer of the present invention in which the active ingredient has a specific particle size distribution, the active ingredient can reach the respiratory organs of the recipient, especially the upper respiratory tract or the lungs, thereby maintaining high and long-term resistance. Influenza activity.
本發明之噴霧器用組成物於投予至接受者之際，因作成等張液，故減輕對呼吸器官組織的刺激。 The composition for a nebulizer of the present invention forms an isotonic solution when administered to a recipient, thereby reducing irritation to respiratory organ tissues.
迄今，尚未知悉將吸入液劑作為冷凍乾燥製劑者。本發明之冷凍乾燥製劑則於物理的安定性為優異，使用於常溫常壓保存6個月以上的該冷凍乾燥製劑而調製的本發明之噴霧器用組成物係顯示優異的噴霧性。 To date, no inhalation solution is known as a freeze-dried formulation. The freeze-dried preparation of the present invention is excellent in physical stability, and the nebulizer composition of the present invention prepared by using the freeze-dried preparation stored at normal temperature and pressure for 6 months or more exhibits excellent sprayability.
為本發明之噴霧器用組成物之有效成分的拉尼娜米韋辛酸酯水合物、或其藥理上可容許的鹽，可按照國際公開第2008/126943號小冊或國際公開第2013/089168號小冊揭露的方法或依據其之方法而製造。 La Nina mivir octanoate hydrate, which is an active ingredient of the composition for a nebulizer of the present invention, or a pharmacologically acceptable salt thereof, can be prepared in accordance with International Publication No. 2008/126943 Pamphlet or International Publication No. 2013/089168 Pamphlet. methods disclosed in the booklet or manufactured in accordance with the methods thereof.
本發明之噴霧器用組成物之有效成分係如前述，利用雷射繞射散射式粒度分布測定法之50重量%之有效成分的粒徑為5.0μm以下，且利用雷射繞射散射式粒度分布測定法之90重量%之有效成分的粒徑為12.0μm以下者為較佳。再者，利用雷射繞射散射式粒度分布測定法之50重量%之有效成分的粒徑為3.2μm以下，且利用雷射繞射散射式粒度分布測定法之90重量%之有效成分的粒徑為8.0μm以下者為更佳。此種粒徑之拉尼娜米韋辛酸酯水合物、或其藥理上可容許的鹽係可按照國際公開第2008/126943號小冊或國際公開第2013/089168號小冊所揭露的方法或依據其之方法來製造。 The active ingredient of the composition for nebulizer of the present invention is as described above, the particle size of 50% by weight of the active ingredient is 5.0 μm or less by the laser diffraction scattering particle size distribution measurement method, and the particle size distribution by the laser diffraction scattering particle size distribution is 5.0 μm or less. The particle size of 90% by weight of the active ingredient in the measurement method is preferably 12.0 μm or less. Furthermore, the particle size of 50% by weight of the active ingredient using the laser diffraction scattering particle size distribution measurement method is 3.2 μm or less, and the particle size of 90% by weight of the active ingredient using the laser diffraction scattering particle size distribution measurement method. More preferably, the diameter is 8.0 μm or less. La Nina mivir octanoate hydrate with such particle size, or a pharmacologically acceptable salt thereof, can be prepared according to the method or basis disclosed in International Publication No. 2008/126943 or International Publication No. 2013/089168. its method of manufacture.
本發明之冷凍乾燥製劑可藉由以下所述的方法來製造。 The freeze-dried preparation of the present invention can be produced by the method described below.
將藉由上述之國際公報所揭露的方法或依據其之方法而製造規定之粒徑的有效成分，藉由氣流粉碎機(jet mill)等之乾式粉碎法而加以微粒子化。接著，將經微粒子化的有效成分，依據使分散劑與浸透壓調節劑溶解而獲得的溶液，藉由Physcotron等之均質機、或EmulsiFlex、微射流均質機(microfluidizer)等之高壓均質機而使有效成分之微粒子分散，接著將獲得的混合液填充於容器，使冷凍乾燥而作成冷凍乾燥製劑。 The active ingredient having a predetermined particle size produced by the method disclosed in the above-mentioned International Gazette or the method according to the above-mentioned method is made into fine particles by a dry pulverization method such as a jet mill. Next, the micronized active ingredient is prepared by a homogenizer such as Physcotron, or a high-pressure homogenizer such as EmulsiFlex or a microfluidizer, based on a solution obtained by dissolving a dispersant and an osmotic pressure regulator. The fine particles of the active ingredient are dispersed, and then the obtained mixed solution is filled in a container and freeze-dried to prepare a freeze-dried preparation.
或者，合併微粒子化的有效成分、與將分散劑溶解於純水者，並藉由Physcotron等之均質機、或EmulsiFlex、微射流均質機等之高壓均質機而使有效成分之微粒子分散。接著將獲得的懸浮液填充於容器，使冷凍乾燥而作成冷凍乾燥製劑。 Alternatively, the fine particles of the active ingredient are dispersed by a homogenizer such as a Physcotron or a high pressure homogenizer such as an EmulsiFlex or a microjet homogenizer by combining the micronized active ingredient and dissolving the dispersant in pure water. Next, the obtained suspension was filled in a container and freeze-dried to prepare a freeze-dried preparation.
此方法為用於冷凍乾燥製劑中僅包含有效成分及分散劑的情形的製造方法。 This method is a production method used when only an active ingredient and a dispersant are contained in a freeze-dried preparation.
如此製造的本發明之冷凍乾燥製劑係藉由於被封入的容器中添加懸浮用液而分散，被調製成噴霧器用組成物。 The freeze-dried preparation of the present invention thus produced is dispersed by adding a suspension liquid to a sealed container, and prepared as a composition for a nebulizer.
於冷凍乾燥製劑中包含有效成分、分散劑、浸透壓調節劑的情形，懸浮用液係純水為較佳。 When an active ingredient, a dispersant, and an osmotic pressure regulator are contained in the freeze-dried preparation, the suspension liquid is preferably pure water.
於冷凍乾燥製劑中僅包含有效成分及分散劑的情形，使用浸透壓調節劑之水溶液作為懸浮用液。就具體例而言，可列舉氯化鈉之水溶液、或生理食鹽水。 In the case where only the active ingredient and the dispersing agent are contained in the freeze-dried preparation, an aqueous solution of the osmotic pressure regulator is used as the suspension liquid. Specific examples include an aqueous solution of sodium chloride or a physiological saline solution.
如此製造的本發明之噴霧器用組成物係懸浮液狀之水性液劑。 The thus-produced composition for a nebulizer of the present invention is an aqueous liquid preparation in the form of a suspension.
如此製造的本發明之噴霧器用組成物係使用噴霧器，較佳為噴射式噴霧器(亦稱為壓縮機式噴霧器)，而被投予至接受者。 The thus-produced composition for a nebulizer of the present invention is administered to a recipient using a nebulizer, preferably a jet nebulizer (also referred to as a compressor nebulizer).
本發明之噴霧器用組成物之投予量係將拉尼娜米韋辛酸酯以無水物換算計，每1次之投予，較佳為40~320mg，更佳為80~160mg，特佳為160mg。 The dosage of the composition for nebulizer of the present invention is based on the conversion of La Nina mivir octanoate to anhydrous, and each dosage is preferably 40-320 mg, more preferably 80-160 mg, and particularly preferably 160 mg .
本發明之噴霧器用組成物之投予量，具體而言，將拉尼娜米韋辛酸酯以無水物換算，每1次之投予，例如為80mg、160mg、240mg、320mg，較佳為80mg、160mg，特佳為160mg。 The dosage of the composition for a nebulizer of the present invention, specifically, converts laninamivir octanoate to anhydrous, and each administration is, for example, 80 mg, 160 mg, 240 mg, 320 mg, preferably 80 mg, 160mg, preferably 160mg.
將本發明之噴霧器用組成物作為流行性感冒病毒感染症之預防劑投予的情形，對流行性感冒病毒感染症之發症前的人類呼吸器官組織，間歇地投予。每1次之投予，吸入上述之投予量。投予間隔係例如，5~10日、或1週。 When the composition for a nebulizer of the present invention is administered as a preventive agent for influenza virus infection, it is intermittently administered to human respiratory tissues before the onset of influenza virus infection. For each dose, inhale the above dose. The administration interval is, for example, 5 to 10 days, or 1 week.
其中，發病前係指不論病毒感染之有無，未觀察到流行性感冒症狀的狀態。 Among them, pre-onset refers to a state in which influenza symptoms are not observed regardless of the presence or absence of viral infection.
於實際之醫療現場，不管是否感染流行性感冒病毒，有將於流行性感冒症狀發病前投予作為預防投予的情形。於本發明之預防劑之投予時期，不管是否有無感染，亦包含於發病前投予。 In the actual medical field, regardless of whether the influenza virus is infected or not, it may be administered as a preventive administration before the onset of influenza symptoms. The administration period of the preventive agent of the present invention, regardless of whether there is infection or not, also includes administration before the onset of the disease.
將本發明之噴霧器用組成物作為流行性感冒病毒感染症之治療劑來投予的情形，對流行性感冒病毒 感染症之發病時的人類之呼吸器官組織，藉由1次之投予而吸入上述之投予量。 When the nebulizer composition of the present invention is administered as a therapeutic agent for influenza virus infection, the The human respiratory tissue at the time of the onset of the infectious disease is inhaled the above-mentioned dose by one dose.
發病時係指有流行性感冒病毒感染，且觀察到發熱等之自覺症狀。 At the time of onset, it means that there is influenza virus infection, and subjective symptoms such as fever are observed.
吸入液劑之投予之際，為吸入用裝置的噴霧器係有必要的，即使於不具有此種裝置的接受者，本發明之噴霧器用組成物因1次投予即結束，不需要重複地回到醫院，接受者之返回醫院的負擔亦少。因以1次的投予即治療結束，於現在市售的神經胺酸酶抑制劑之中，與噴霧器之組合作成製品者僅為拉尼娜米韋辛酸酯水合物。 When the inhalation liquid is administered, a nebulizer, which is an inhalation device, is necessary. Even in a recipient who does not have such a device, the composition for a nebulizer of the present invention ends after one administration, and does not need to be repeated. Returning to the hospital, the recipient's burden of returning to the hospital is also less. Since the treatment ends with one administration, among the currently available neuraminidase inhibitors, the only product that is combined with a nebulizer is La Nina mivir octanoate hydrate.
以下呈示實施例及試驗例，進一步詳細說明本發明。 Examples and test examples are shown below, and the present invention is further described in detail.
(實施例1~3)噴霧器用組成物之製造 (Examples 1 to 3) Manufacture of composition for nebulizer
將按照國際公開第2008/126943號所記載的製造方法所製造的拉尼娜米韋辛酸酯水合物之結晶(以下，稱為有效成分)，以氣流粉碎機法(超音速噴射粉碎機(型式PJM-100SP)、日本Pneumatic工業股份有限公司)加以粉碎，獲得表1所示的粒徑分布之粉碎物。 The crystals of La Nina mivir octanoate hydrate (hereinafter, referred to as active ingredients) produced by the production method described in International Publication No. 2008/126943 were subjected to a jet mill method (supersonic jet mill (type PJM). -100SP), Japan Pneumatic Industrial Co., Ltd.) was pulverized to obtain a pulverized product with a particle size distribution shown in Table 1.
其次，將作為分散劑之規定量之羥基丙基甲基纖維素、作為浸透壓調節劑之乳糖水合物或氯化鈉溶解於純水者、與規定量之有效成分合併，以均質機(Physcotron(型式：NS-50)、日音醫理科器械製作所(股))預先分散，接著，以高壓均質機(微射流均質機(型式：M-110EH)、Powrex股份有限公司)分散，獲得實施例1~3之懸浮液狀 之組成物。將獲得的組成示於表2。 Next, a predetermined amount of hydroxypropyl methylcellulose as a dispersing agent, lactose hydrate as an osmotic pressure regulator or sodium chloride dissolved in pure water, and a predetermined amount of active ingredients are combined with a homogenizer (Physcotron (Type: NS-50), Nihon Medical & Scientific Instrument Manufacturing Co., Ltd. (stock)) was pre-dispersed, and then dispersed with a high-pressure homogenizer (micro-jet homogenizer (type: M-110EH), Powrex Co., Ltd.) to obtain Examples 1~3 of the suspension composition. The obtained composition is shown in Table 2.
(實施例4、5)噴霧器用組成物之製造 (Examples 4 and 5) Manufacture of composition for nebulizer
將作為分散劑之規定量的聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)、山梨醇酐單月桂酸酯(Span 20)及氯化鈉溶解於純水，與規定量之粉碎的有效成分合併，以均質機(Physcotron)(NS-50、日音醫理科器械製作所(股))事先分散，接著以微射流均質機(M-110EH、Powrex股份有限公司)分散，而獲得實施例4、5之懸浮液狀之組成物。將獲得的組成示於表3。 Dissolving predetermined amounts of polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan monolaurate (Span 20) and sodium chloride in pure water as dispersants is effective for pulverizing the predetermined amount. The ingredients were combined and dispersed in advance with a homogenizer (Physcotron) (NS-50, Nihon Medical & Scientific Instrument Manufacturing Co., Ltd.), and then dispersed with a microfluidizer (M-110EH, Powrex Co., Ltd.) to obtain Example 4 , 5 of the composition of the suspension. The obtained composition is shown in Table 3.
(比較例1)將Inavir(商標名)吸入粉末劑以純水加以分散的組成物 (Comparative Example 1) Composition in which Inavir (trade name) inhalation powder was dispersed in pure water
被市售的Inavir(商標名)吸入粉末劑20mg係由拉尼娜米韋辛酸酯水合物與乳糖水合物所構成的組成物。取此粉末400mg，以純水8mL加以分散，而獲得比較例1之組成物。將獲得的組成示於表4。於此粉末400mg中，包含80mg作為無水物之拉尼娜米韋辛酸酯水合物。 The commercially available Inavir (trade name) inhalation powder 20 mg is a composition consisting of laninamivir caprylate hydrate and lactose hydrate. 400 mg of this powder was taken and dispersed in 8 mL of pure water to obtain the composition of Comparative Example 1. The obtained composition is shown in Table 4. In 400 mg of this powder, 80 mg of laninamivir octanoate hydrate is contained as an anhydrous.
(比較例2~3)僅分散劑之組成物 (Comparative Examples 2 to 3) Dispersant-only compositions
將作為分散劑之聚氧乙烯山梨醇酐單油酸酯(Tween 80)及/或羧基甲基纖維素鈉(CMCNa)溶解於純水，與規定量之經粉碎的有效成分一起，以均質機(Physcotron(型式：NS-50)、日音醫理科器械製作所(股))事先分散，接著，以高壓均質機(微射流均質機(型式：M-110EH)、Powrex股份有限公司)加以分散，而獲得懸浮液狀之組成物。將獲得的組成示於表5。 Dissolve polyoxyethylene sorbitan monooleate (Tween 80) and/or sodium carboxymethyl cellulose (CMCNa) as a dispersant in pure water, and mix with a predetermined amount of the pulverized active ingredients in a homogenizer. (Physcotron (type: NS-50), Nihon Medical and Scientific Instrument Manufacturing Co., Ltd. (stock)) was dispersed in advance, and then dispersed with a high-pressure homogenizer (micro-jet homogenizer (type: M-110EH), Powrex Co., Ltd.), A suspension-like composition was obtained. The obtained composition is shown in Table 5.
(實施例6、7)噴霧器用組成物與冷凍乾燥製 劑之製造 (Examples 6, 7) Composition for sprayer and freeze-dried preparation Manufacture of the agent
將作為分散劑之規定量的泰洛沙泊，與作為浸透壓調節劑之規定量之氯化鈉溶解於純水者加以混合，與規定量之粉碎的有效成分合併，以攪拌機(MAZELA Z(型式：Z-1100)、EYELA)事先分散，接著，以高壓均質機(微射流均質機(型式：H-110EH)、Powrex股份有限公司)加以分散，獲得實施例6之懸浮液狀之組成物。又，將獲得的組成物使用冷凍乾燥機(Triomaster II A-04、共和真空)進行冷凍乾燥，而獲得實施例7之冷凍乾燥製劑。將獲得的製劑之組成示於表6。 A prescribed amount of tyloxapol as a dispersing agent and a prescribed amount of sodium chloride as an osmotic pressure regulator dissolved in pure water are mixed, combined with a prescribed amount of the pulverized active ingredients, and mixed with a mixer (MAZELA Z (MAZELA Z) Type: Z-1100), EYELA) were dispersed in advance, then, dispersed with a high-pressure homogenizer (micro-jet homogenizer (type: H-110EH), Powrex Co., Ltd.) to obtain the suspension-like composition of Example 6 . Furthermore, the obtained composition was freeze-dried using a freeze dryer (Triomaster II A-04, Kyodo vacuum), and the freeze-dried preparation of Example 7 was obtained. The composition of the obtained preparation is shown in Table 6.
(實施例8~14)噴霧器用冷凍乾燥製劑之製造 (Examples 8 to 14) Production of freeze-dried formulations for sprayers
將作為分散劑之規定量的泰洛沙泊溶解於純水，與規定量之經粉碎的有效成分合併，以攪拌機(MAZELA Z(型式：Z-1100)、EYELA)預先分散，接著以高壓均質機(壓力式均質機(型式：LAB1000)、SMT股份有限公司)分散，使用冷凍乾燥機(Triomaster IIA-04、共和真空)將獲得的混合物加以冷凍乾燥，獲得實施例8~14之冷凍乾燥製劑。將獲得的冷凍乾燥製劑之組成示於表7。 A predetermined amount of tyloxapol as a dispersant was dissolved in pure water, combined with a predetermined amount of the pulverized active ingredient, pre-dispersed with a mixer (MAZELA Z (type: Z-1100), EYELA), and then homogenized by high pressure machine (pressure homogenizer (type: LAB1000), SMT Co., Ltd.) to disperse, and freeze-dry the obtained mixture using a freeze dryer (Triomaster IIA-04, Kyodo vacuum) to obtain the freeze-dried preparations of Examples 8 to 14. . The composition of the obtained freeze-dried preparation is shown in Table 7.
(實施例15~22)噴霧器用組成物之調製 (Examples 15 to 22) Preparation of composition for nebulizer
將純水添加至實施例7所獲得的冷凍乾燥製劑，將生理食鹽水添加至實施例8~14所獲得的冷凍乾燥製劑並加以分散，獲得實施例15~22之噴霧器用組成物。將獲得的組成示於表8。 Pure water was added to the freeze-dried preparations obtained in Example 7, and physiological saline was added to the freeze-dried preparations obtained in Examples 8 to 14 and dispersed to obtain the sprayer compositions of Examples 15 to 22. The obtained composition is shown in Table 8.
(實施例23~25)有效成分含量不同的組成物之調製 (Examples 23 to 25) Preparation of compositions with different active ingredient contents
將實施例9之冷凍乾燥製劑以生理食鹽水4mL加以分散後，將2mL注入噴霧器而作成含有40mg有效成分的製劑作為實施例23，將實施例9之冷凍乾燥製劑以生理食鹽水1mL加以分散者兩個合併注入噴霧器者作為實施例24，將實施例9之冷凍乾燥製劑以生理食鹽水0.5mL加以 分散者四個合併注入噴霧器者作為實施例25，而獲得噴霧器用之吸入液劑。又，有效成分量係表示呈無水物之重量。將獲得的組成示於表9。 After dispersing the freeze-dried preparation of Example 9 with 4 mL of physiological saline, 2 mL was injected into a nebulizer to prepare a preparation containing 40 mg of the active ingredient as Example 23, and the freeze-dried preparation of Example 9 was dispersed with 1 mL of physiological saline Two combined injectors were used as Example 24, and the freeze-dried preparation of Example 9 was added with 0.5 mL of physiological saline. Four of the dispersers were combined into a nebulizer as Example 25 to obtain an inhalation solution for a nebulizer. In addition, the amount of an active ingredient means the weight in the form of anhydrous. The obtained composition is shown in Table 9.
(實施例26~28)噴霧器用冷凍乾燥製劑之製造 (Examples 26 to 28) Production of freeze-dried formulations for sprayers
將作為分散劑之規定量的泰洛沙泊溶解於純水，與以氣流粉碎機法(超音速噴射粉碎機(型式PJM-100SP)、日本Pneumatic工業股份有限公司)粉碎的規定量之有效成分合併，以攪拌機(密封攪拌機(型式：RC-60G5-2S)、MAGNEO GIKEN)預先分散，接著，以高壓均質機(壓力式均質機(型式：R5-10.38)、SMT股份有限公司)加以分散，將獲得的混合物使用冷凍乾燥機(冷凍真空乾燥裝置(型式DFB3055-2BS-ST/CIP)、ULVAC股份有限公司)進行冷凍乾燥，獲得實施例26~28之冷凍乾燥製劑。將獲得的冷凍乾燥製劑之組成示於表10。 A prescribed amount of tyloxapol as a dispersant was dissolved in pure water, and the prescribed amount of the active ingredient was pulverized by a jet mill method (supersonic jet mill (type PJM-100SP), Japan Pneumatic Industry Co., Ltd.) Combined, pre-dispersed with a mixer (sealed mixer (type: RC-60G5-2S), MAGNEO GIKEN), and then dispersed with a high-pressure homogenizer (pressure homogenizer (type: R5-10.38), SMT Co., Ltd.), The obtained mixture was freeze-dried using a freeze dryer (freeze vacuum drying device (type DFB3055-2BS-ST/CIP), ULVAC Co., Ltd.) to obtain freeze-dried preparations of Examples 26 to 28. The composition of the obtained freeze-dried preparation is shown in Table 10.
(實施例29~35)有效成分含量不同的組成物之調製 (Examples 29 to 35) Preparation of compositions with different active ingredient contents
將實施例26之冷凍乾燥製劑以生理食鹽水4mL加以分散後，將2mL注入噴霧器，將含有40mg有效成分的噴霧器用組成物者作為實施例29，將實施例26之冷凍乾燥製劑以生理食鹽水2mL加以分散而注入噴霧器，將含有80mg有效成分的噴霧器用組成物作為實施例30，將實施例26之冷凍乾燥製劑以生理食鹽水1mL加以分散者兩個合併注入噴霧器，將含有160mg有效成分的噴霧器用組成物者作為實施例31，將實施例26之冷凍乾燥製劑以生理食鹽水1mL加以分散者3個合併注入噴霧器，將含有240mg的有效成分的噴霧器用組成物作為實施例32，將實施例26之冷凍乾燥製劑以生理食鹽水1mL加以分散者4個合併而注入噴霧器，將含有320mg有效成分的噴霧器用組成物者作為實施例33，將實施例27之冷凍燥製劑以生理食鹽水2mL加以分散而注入噴霧器，作為含有80mg有效成分的噴霧器用組成物者作為實施例34，將實施例28之冷凍乾燥製劑以生理食鹽水2mL加以分散而注入噴霧器，作為含有160mg有效成分的噴霧器用組成物者作為實施例35。又，有效成分量係表示呈無水物之重量。 將獲得的組成示於表11。 After the freeze-dried preparation of Example 26 was dispersed with 4 mL of physiological saline, 2 mL was injected into the nebulizer, and the composition for the nebulizer containing 40 mg of the active ingredient was taken as Example 29, and the freeze-dried preparation of Example 26 was treated with physiological saline. 2mL was dispersed and injected into the sprayer, the composition for the sprayer containing 80mg of active ingredient was used as Example 30, and the freeze-dried preparation of Example 26 was added with 1mL of physiological saline and the two were combined into the sprayer. The composition for a nebulizer was taken as Example 31, and the freeze-dried preparation of Example 26 was dispersed in 1 mL of physiological saline and injected into a nebulizer, and the composition for a nebulizer containing 240 mg of the active ingredient was taken as Example 32. The freeze-dried preparation of Example 26 was mixed with 1 mL of physiological saline and injected into a nebulizer. The nebulizer composition containing 320 mg of the active ingredient was used as Example 33, and the freeze-dried preparation of Example 27 was mixed with 2 mL of physiological saline. Dispersed and injected into a nebulizer, as the composition for a nebulizer containing 80 mg of the active ingredient as Example 34, the freeze-dried preparation of Example 28 was dispersed with 2 mL of physiological saline and injected into the nebulizer, as the composition for a nebulizer containing 160 mg of the active ingredient as Example 35. In addition, the amount of an active ingredient means the weight in the form of anhydrous. The obtained composition is shown in Table 11.
(試驗方法)藥劑之呼吸器官到達性評價(微粒子量之測定法) (Test method) Evaluation of drug reachability to respiratory organs (measurement method for the amount of fine particles)
作為活體外簡易地評價吸入液劑之呼吸器官到達性的方法，已廣泛使用利用次世代撞擊器(next generation impactor(NGI))的微粒子量之測定法(例如，參照USP37、<1601>噴霧用產物-特性試驗、或歐洲藥典7.3、2.9.44.噴霧用製劑：特性)。 As a method for simply evaluating the respiratory reachability of inhaled liquid preparations in vitro, a method for measuring the amount of fine particles using a next generation impactor (NGI) has been widely used (for example, refer to USP37, <1601> for spraying) Product-Characteristic Test, or European Pharmacopoeia 7.3, 2.9.44. Formulations for Spray: Properties).
此方法係使用將由吸入用器具藉由泵被吸引導入至撞擊器內的藥劑粒子加以分級的裝置。被吸引的 藥劑係因應粒徑而到達構成撞擊器的10個部分(接口管接合器(mouthpiece adapter)、進氣口(induction port)、1~7級、微孔收集器(micro-orifice collector,MOC))之任一者。於接口管接合器、進氣口收集凝集塊等大粒子。另一方面，粒徑小的藥劑粒子雖到達1級~MOC中任一者，但粒徑越小到達編號越大的級，於MOC收集通過7級的藥劑粒子。 This method uses a device for classifying the drug particles that are sucked and introduced into the impactor by the inhalation device by means of a pump. attracted The agent reaches 10 parts (mouthpiece adapter, induction port, stage 1~7, micro-orifice collector, MOC) that make up the impactor according to the particle size either. Collect large particles such as agglomerates at mouthpiece adapters and air inlets. On the other hand, the chemical particles with small particle diameters reach any one of the 1st to the MOC, but the smaller the particle size reaches the higher-numbered stages, and the chemical particles passing through the 7th stage are collected at the MOC.
利用調查藥劑粒徑與以伽馬閃爍顯像術(gamma scintigraphy)測定的藥劑至呼吸器官的送達量之相關性的文獻(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.)時，粒徑3μm至5μm以下之藥劑的量係與藥劑之至呼吸器官的送達量有相關。將本發明之噴霧器用組成物中含有的有效成分量中空力學的粒徑為4.4μm以下之有效成分量定義為微粒子量(fine particle dose：FPD)，使用此參數來評價呼吸器官到達性。 Utilize a literature that investigates the correlation between the particle size of the drug and the delivery of the drug to the respiratory organs measured by gamma scintigraphy (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.) At this time, the amount of the drug with a particle size of 3 μm to 5 μm or less is related to the delivery amount of the drug to the respiratory organs. The amount of active ingredient contained in the composition for a nebulizer of the present invention is defined as the amount of active ingredient having a hollow particle diameter of 4.4 μm or less as a fine particle dose (FPD), and this parameter is used to evaluate the respiratory organ reachability.
此評價由於係微粒子量之評價，於以下之試驗例中，亦記載為微粒子量評價。又，各種噴霧器用組成物之噴霧係使用壓縮機式噴霧器裝置(壓縮機：PARI BOYN(PARI Japan)、噴霧器：PARI‧LC PLUS(PARI Japan))來進行。 Since this evaluation is an evaluation of the amount of fine particles, in the following test examples, it is also described as the evaluation of the amount of fine particles. In addition, the spraying of the composition for various sprayers was performed using a compressor type sprayer device (compressor: PARI BOYN (PARI Japan), sprayer: PARI·LC PLUS (PARI Japan)).
(試驗例1)將Inavir吸入粉末劑以純水分散的 情形之微粒子量評價 (Test Example 1) Inavir inhalation powder was dispersed in pure water Situational particle size evaluation
表12顯示進行將Inavir吸入粉末劑20mg之粉末400mg(包含呈無水物之有效成分80mg)以純水8mL分散的液體之微粒子量評價之結果。微粒子量(FPD)僅0.4mg。 Table 12 shows the results of evaluating the particle size of a liquid in which 20 mg of Inavir inhalation powder was dispersed in 400 mg of the powder (including 80 mg of the active ingredient as anhydrous) in 8 mL of pure water. The fine particle size (FPD) is only 0.4 mg.
(試驗例2)僅分散劑之懸浮液 (Test Example 2) Dispersant-only suspension
將於比較例2及3所獲得的組成物之微粒子量評價結果示於表13。 Table 13 shows the results of evaluating the amount of fine particles of the compositions obtained in Comparative Examples 2 and 3.
(試驗例3)浸透壓調節劑之影響 (Test Example 3) Influence of osmotic pressure regulator
將於實施例1~3所獲得的組成物之微粒子量評價結果示於表14。除了分散劑羥基丙基甲基纖維素，藉由添加乳糖水合物或氯化鈉，顯示良好的微粒子量。 Table 14 shows the results of evaluating the amount of fine particles of the compositions obtained in Examples 1 to 3. In addition to the dispersant hydroxypropyl methylcellulose, by adding lactose hydrate or sodium chloride, a good particle size was shown.
(試驗例4)分散劑之影響 (Test Example 4) Influence of dispersing agent
與試驗例3同樣地，對於實施例4、5所獲得之添加作為分散劑之聚氧乙烯山梨醇酐單月桂酸酯(Tween 20)及山梨醇酐單月桂酸酯(Span 20)的組成物評價微粒子量。將結果示於表15。於添加兩物質作為分散劑的系統亦顯示良好的微粒子量。 In the same manner as in Test Example 3, the compositions obtained in Examples 4 and 5 were obtained by adding polyoxyethylene sorbitan monolaurate (Tween 20) and sorbitan monolaurate (Span 20) as dispersants. Evaluate the amount of fine particles. The results are shown in Table 15. The system with the addition of the two substances as dispersants also showed good particle size.
(試驗例5)冷凍乾燥製劑之微粒子量評價 (Test Example 5) Evaluation of microparticle size of freeze-dried preparations
調製摻合作為分散劑之泰洛沙泊、作為浸透壓調節劑之氯化鈉之水溶液的組成物，評價懸浮液之狀態(實施例6)及將冷凍乾燥製劑分散於純水的狀態(實施例15)之微粒子量。將結果示於表16。作為懸浮液被製造的組成物、及冷凍乾燥後以氯化鈉之水溶液使分散的組成物皆顯示良好的微粒子量。 A composition containing tyloxapol as a dispersant and an aqueous solution of sodium chloride as an osmotic pressure regulator was prepared, and the state of the suspension (Example 6) and the state of the freeze-dried preparation dispersed in pure water (Example 6) were prepared. Example 15) the amount of fine particles. The results are shown in Table 16. Both the composition produced as a suspension and the composition dispersed with an aqueous solution of sodium chloride after freeze-drying showed a good amount of fine particles.
(試驗例6)冷凍乾燥製劑之安定性評價 (Test Example 6) Stability evaluation of freeze-dried preparations
進行實施例7之冷凍乾燥製劑之安定性評價。微粒子量之評價係以與實施例15相同的方法作成噴霧器用組成物，以上述之方法來進行。不純物之評價係利用HPLC法來進行。將結果示於表17。本劑被確認至6個月為止為安定的。 Stability evaluation of the freeze-dried formulation of Example 7 was performed. The evaluation of the amount of fine particles was carried out in the same manner as in Example 15 to prepare a composition for a nebulizer and by the above-mentioned method. The evaluation of the impurity was performed by the HPLC method. The results are shown in Table 17. This agent was confirmed to be stable up to 6 months.
(試驗例7)包含各種泰洛沙泊摻合量與具有 各種粒徑的有效成分之組成物的微粒子量評價 (Test Example 7) Including various blending amounts of tyloxapol and Evaluation of fine particle size of compositions of active ingredients of various particle sizes
以含有作為分散劑之泰洛沙泊之組成物，評價使有效成分之粒徑變化時之微粒子量。將結果示於表18。於本實施例中之泰洛沙泊量與有效成分之粒徑範圍顯示良好的微粒子量。 With the composition containing tyloxapol as a dispersant, the amount of fine particles when the particle diameter of the active ingredient was changed was evaluated. The results are shown in Table 18. In this example, the amount of tyloxapol and the particle size range of the active ingredient showed a good amount of fine particles.
(試驗例8) (Test Example 8)
將實施例9所獲得的冷凍乾燥製劑以純水分散者作為比較例4，與實施例17所獲得的組成物比較微粒子量。將結果示於表19。藉由添加作為浸透壓調節劑之氯化鈉，顯示微粒子量提升。 The freeze-dried preparation obtained in Example 9 was dispersed in pure water as Comparative Example 4, and the amount of fine particles was compared with the composition obtained in Example 17. The results are shown in Table 19. By adding sodium chloride as an osmotic pressure regulator, the amount of fine particles was shown to increase.
(試驗例9) (Test Example 9)
將實施例17、實施例23~25、實施例30、及實施例34~35之微粒子量評價結果示於表20。顯示伴隨有效成分含量之增加，FPD亦增加。 Table 20 shows the evaluation results of the amount of fine particles in Example 17, Examples 23 to 25, Example 30, and Examples 34 to 35. It was shown that with the increase of the active ingredient content, the FPD also increased.
(試驗例10)健康成人男性對象之藥物動態的研討試驗 (Example 10) Study of drug dynamics in healthy adult male subjects
將日本人健康成人男性作為對象，使用噴霧器將含有有效成分的噴霧器用組成物進行單次吸入投予，而研討有效成分、及有效成分之活性代謝物的前述之化合物(III)(以下，亦記載為活性代謝物)之血漿中及肺泡內之藥物動態。 The above-mentioned compound (III) (hereinafter, also referred to as the active metabolite) of the active ingredient and the active metabolite of the active ingredient was studied by taking a single inhalation administration of a nebulizer composition containing an active ingredient using a nebulizer for Japanese healthy adult males. The pharmacokinetics in plasma and in the alveoli were reported as active metabolites.
於有效成分之吸入投予前後進行採血，測定血漿中之藥物濃度。又，將有效成分吸入投予後進行肺泡內洗淨，測定肺泡黏液及肺泡巨噬細胞中之藥物濃度。藥物濃度係以有效成分及活性代謝物作為對象來進行。藥物濃度之測定係使用經驗證的液體層析串聯質譜法。 Blood was collected before and after the inhalation administration of the active ingredient, and the drug concentration in the plasma was determined. In addition, after the active ingredient was inhaled and administered, the alveoli were washed, and the drug concentration in the alveolar mucus and alveolar macrophages was measured. The drug concentration was carried out for the active ingredient and active metabolite. Drug concentrations were determined using a validated liquid chromatography tandem mass spectrometry method.
僅評價血漿中藥物動態的情形，投藥係將作為有效成分(顯示呈無水物之重量。以下，於試驗例10係同樣的)之40mg、80mg、160mg、240mg、或320mg作單次投予。於投藥，各自使用按照實施例29、實施例30、實施例31、實施例32、實施例33所調整的噴霧器用組成物。又，評價投予噴霧器用組成物後之安全性。 In the case of evaluating only the pharmacokinetics in plasma, 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg of the active ingredient (shown as anhydrous weight. Hereinafter, the same is applied to Test Example 10) was administered in a single dose. For administration, the nebulizer compositions adjusted according to Example 29, Example 30, Example 31, Example 32, and Example 33 were used, respectively. Furthermore, the safety after administration of the composition for a nebulizer was evaluated.
將日本人健康成人男性作為對象，將含有效成分的組成物，使用噴霧器作單次吸入投予時之血漿中的活性代謝物之濃度係最高血漿中濃度到達時間(Tmax、中央值)為4.0~6.0小時，消失半衰期(T1/2、平均值)為58.29~165.8小時。血漿中之活性代謝物之最高血漿中濃度(Cmax)及投予後之血漿中濃度下面積(AUClast)係與投 予量幾乎成比例增大。關於將有效成分量40mg、80mg、160mg、240mg、或320mg之噴霧器用組成物單次投予時之安全性，自生命徵象、誘導心電圖之計測，未觀察到成為安全性上問題的見解。 The concentration of the active metabolite in the plasma at the time of single inhalation administration of the composition containing the active ingredient using a nebulizer for healthy Japanese adult males is the time to reach the highest plasma concentration (Tmax, median value) of 4.0 ~6.0 hours, and the disappearance half-life (T 1/2 , mean) was 58.29 to 165.8 hours. The maximum plasma concentration (Cmax) of the active metabolite in plasma and the area under the plasma concentration after administration (AUClast) increased almost proportional to the dose administered. 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, there is no opinion that it is a safety problem from the measurement of vital signs and induced electrocardiogram.
評價肺泡內之藥物動態的情形，投藥係將作為有效成分之160mg作單次投予。於投藥，使用按照實施例31所調整的噴霧器用組成物。 To evaluate the dynamics of the drug in the alveoli, the administration was performed by a single dose of 160 mg as an active ingredient. For administration, the composition for a nebulizer adjusted according to Example 31 was used.
又，評價投予噴霧器用組成物後之安全性。 Furthermore, the safety after administration of the composition for a nebulizer was evaluated.
將有效成分單次吸入投予後，使用支氣管肺泡洗淨(bronchoalveolar lavage：BAL)法來進行肺泡內洗淨，將肺泡內洗淨液回收，而測定肺泡黏液及肺泡巨噬細胞中之藥物濃度。肺泡黏液中之活性代謝物濃度係於最初之測定時點(投予開始4小時後)顯示最高濃度。其濃度為1459ng/mL，以活性代謝物之分子量(346.34)換算時，為約4.2μM。投予開始168小時後之濃度為636.1ng/mL(約1.8μM)。 After a single inhalation administration of the active ingredient, the bronchoalveolar lavage (BAL) method was used to wash the alveoli, and the alveolar wash was recovered to measure the drug concentration in alveolar mucus and alveolar macrophages. The active metabolite concentration in the alveolar mucus showed the highest concentration at the initial measurement time point (4 hours after the start of administration). Its concentration was 1459 ng/mL, which was about 4.2 μM when converted to the molecular weight of the active metabolite (346.34). The concentration 168 hours after the start of administration was 636.1 ng/mL (about 1.8 μM).
此等之值係將A型及B型流行性感冒病毒之對神經胺酸酶的IC50值[A(H1N1)pdm09型：1.70nM、A(H3N2)型：3.98nM、B型：14.86nM]充分地提升(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 derived from the IC50 values of influenza A and B influenza viruses against neuraminidase [A(H1N1)pdm09: 1.70 nM, A(H3N2): 3.98 nM, B: 14.86 nM ] fully elevated (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.).
又，將日本人健康成人男性作為對象之將噴霧器用組成物(有效成分160mg)作單次吸入投予時的肺泡黏液 中之活性代謝物的濃度，係與將已報告的吸入粉末劑(有效成分40mg)作單次吸入投予時的肺泡黏液中之活性代謝物的濃度為相同程度，吸入粉末劑及噴霧器用組成物皆投予有效成分後，歷經長時間維持超過IC50值的濃度(Antimicrobial Agents and Chemotherapy 2012,vol.56,No.7,p3873-3878)。 In addition, the concentration of active metabolites in alveolar mucus when the composition for nebulizer (active ingredient 160 mg) was administered as a single inhalation for healthy Japanese adult males was the same as the reported inhalation powder (effective). The concentration of the active metabolite in the alveolar mucus when administered as a single inhalation was the same, and the inhalation powder and the composition for nebulizer were all administered with the active ingredient, and maintained a concentration exceeding the IC 50 value for a long time ( Antimicrobial Agents and Chemotherapy 2012, vol. 56, No. 7, p3873-3878).
由以上之藥物動態的結果，將作為有效成分之40~320mg，使用噴霧器，對日本人健康成人男性作單次吸入投予時，活性代謝物之血漿中濃度係與投予量約成比例增加，觀察到伴隨投予量之增加的全身性暴露(systemic exposure)。 From the results of the above pharmacokinetics, when 40-320 mg of the active ingredient is administered by a nebulizer to a Japanese healthy adult male as a single inhalation administration, the plasma concentration of the active metabolite is approximately proportional to the dose. , systemic exposure was observed with increasing doses administered.
將作為有效成分之160mg，使用噴霧器，對日本人健康成人男性作單次投予時之肺泡黏液中之活性代謝物，於投予後最初之評價時點(投予開始4小時後)，觀察到充分提升A型及B型流行性感冒病毒之對神經胺酸酶的IC50值的濃度，因其濃度為長時間持續，故顯示表現持續的藥效的可能性。 The active metabolites in the alveolar mucus when 160 mg of the active ingredient was administered to Japanese healthy adult males in a single dose using a nebulizer was observed at the first evaluation point after the administration (4 hours after the start of administration). The concentration of increasing the IC 50 value of influenza A and B influenza viruses against neuraminidase shows the possibility of showing a sustained medicinal effect because the concentration is sustained for a long time.
關於已經市售的Inavir吸入粉末劑20mg之被認可的成人投予量40mg，確認了對A型及B型流行性感冒病毒感染症的治療‧預防效果，再者，因噴霧器用組成物(有效成分160mg)單次投予時之肺泡黏膜中之藥物動態認為未降低吸入粉末劑(有效成分40mg)投予時之曝露，可期待噴霧器用組成物(有效成分160mg)之對A型及B型流行性感冒病毒感染症的治療‧預防效果。 The approved adult dose of 40 mg of the commercially available Inavir inhalation powder 20 mg has been confirmed for the treatment and prevention of influenza A and B influenza virus infections. Furthermore, the composition for nebulizer (effective The pharmacokinetics in the alveolar mucosa at the time of single administration of the ingredient 160 mg) were not considered to reduce the exposure when the inhalation powder (active ingredient 40 mg) was administered. Therapeutic and preventive effects of influenza virus infection.
(試驗例11)健康成人男性對象之噴霧器用組 成物與吸入粉末劑之藥物動態的比較試驗 (Test Example 11) Nebulizer group for healthy adult male subjects Comparison test of pharmacokinetics of finished product and inhalation powder
比較對日本人健康成人男性，將噴霧器用組成物(有效成分量160mg，顯示呈無水物之重量)、及吸入粉末劑(有效成分量40mg，顯示呈無水物之重量)單次吸入投予時之肺泡黏液中之藥物動態。噴霧器用組成物係使用按照實施例31所調整的噴霧器用組成物。吸入粉末劑係使用市售的Inavir吸入粉末劑20mg。將結果示於表21。 When comparing the composition for a nebulizer (160 mg of the active ingredient, the weight of the anhydrous substance) and the powder for inhalation (the amount of the active ingredient: 40 mg, the weight of the anhydrous substance) for a single inhalation administration to a Japanese healthy adult male Drug dynamics in alveolar mucus. As the composition for a nebulizer, the composition for a nebulizer adjusted according to Example 31 was used. The inhalation powder was 20 mg of commercially available Inavir inhalation powder. The results are shown in Table 21.
Cmax、AUCinf、Tmax、及T1/2係顯示推定值(標準誤差)。 Cmax, AUCinf, Tmax, and T1/2 show estimated values (standard errors).
關於有效成分之活性代謝物的肺泡黏液中濃度，最高血漿中濃度(Cmax)雖於吸入粉末劑投予者有顯示高值傾向，但顯示最高血漿中濃度(Cmax)的時點以後，噴霧器用組成物較吸入粉末劑有更高傾向，至無限大時間為止的血漿中濃度-時間曲線下面積(AUCinf)係於噴霧器用組成物者顯示約2.8倍高值，最高血漿中濃度到達時間(Tmax，中央值)及消失半衰期(T1/2，平均值)係於噴霧器用組成物及吸入粉末劑未觀察到有差異。 Regarding the alveolar mucus concentration of the active metabolite of the active ingredient, the highest plasma concentration (Cmax) tends to show a high value in the case of inhalation powder administration, but after the time point when the highest plasma concentration (Cmax) is shown, the composition for nebulizer Compared with the inhalation powder, the area under the plasma concentration-time curve (AUCinf) to infinity is about 2.8 times higher than that of the inhalation powder, and the time to reach the highest plasma concentration (Tmax, The median value) and disappearance half-life (T 1/2 , average value) were not different between the composition for nebulizer and inhalation powder.
將噴霧器用組成物及吸入粉末劑作單次吸入投予的情形之活性代謝物之最高血漿中濃度(Cmax)及至無限大時間為止的血漿中濃度-時間曲線下面積(AUCinf)係於 噴霧器用組成物或吸入粉末劑皆顯示與投予量約略呈比例增加。 The maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUCinf) of the active metabolite in the case of single inhalation administration of the nebulizer composition and inhalation powder are given in Both the nebulizer composition or the inhalation powder showed a roughly proportional increase to the dose administered.
市售之Inavir吸入粉末劑20mg係於將拉尼娜米韋辛酸酯水合物作為有效成分的吸入粉末劑，於10歲以上之兒童與成人被承認的投予量的有效成分量40mg(顯示呈無水物之重量)中，確認流行性感冒病毒感染症之治療‧預防效果。 The commercially available Inavir inhalation powder 20mg is based on the inhalation powder with laninamivir octanoate hydrate as the active ingredient, and the active ingredient amount is 40mg (shown as anhydrous) in the approved dose for children and adults over 10 years old. The weight of the object), the therapeutic and preventive effects of influenza virus infection were confirmed.
如前述之試驗例10所示，於有效成分80mg、160mg、240mg、320mg之噴霧器用組成物，安全性上並無問題。 As shown in the aforementioned Test Example 10, there was no problem in terms of safety in the composition for nebulizers of 80 mg, 160 mg, 240 mg, and 320 mg of the active ingredient.
考慮此等時，於噴霧器用組成物之有效成分量80mg~320mg，暗示顯示流行性感冒治療‧預防效果的可能性。 Taking these into consideration, the active ingredient amount of the composition for nebulizer is 80 mg to 320 mg, suggesting the possibility of showing the effect of treating and preventing influenza.
(試驗例12)兒童及高齡者之換氣功能的研討試驗 (Test Example 12) Research test on ventilation function of children and the elderly
為了設定於成長過程的兒童或換氣功能低下的高齡者之噴霧器用組成物之用法用量，以兒童及高齡者為對象，測定換氣功能。 In order to set the dosage of the composition for nebulizers for growing children or elderly people with low ventilation function, the ventilation function was measured for children and elderly people.
以健康的1歲以上12歲以下之兒童、75歲以上之高齡者作為對象。又，加上以20歲以上40歲以下之成人作為對照。將結果示於表22。 For healthy children over 1 year old but under 12 years old, and elderly people over 75 years old. In addition, adults over the age of 20 but under the age of 40 were used as controls. The results are shown in Table 22.
平均值(最小值、最大值) Average (min, max)
1歲~12歲兒童之一次換氣量、1分鐘之換氣量(分時換氣量)可見伴隨年齡增加的傾向。於參與此試驗的兒童中，於流行性感冒病毒感染症發病者，測定罹患時之換氣量，與正常時之換氣量作比較，結果不認為有大的不同。將結果示於表23。 One-time ventilation volume and 1-minute ventilation volume (time-sharing ventilation volume) in children aged 1 to 12 years tended to increase with age. Among the children who participated in this experiment, the ventilation volume at the time of suffering was measured in the patients with influenza virus infection, and compared with the ventilation volume at the normal time, the results were not considered to be significantly different. The results are shown in Table 23.
據此，暗示即使兒童有流行性感冒病毒感染症發病的情形，亦無極端地換氣量降低的狀況。 Accordingly, even if a child develops an influenza virus infection, it is suggested that there is no extreme decrease in the ventilation rate.
關於市售之Inavir吸入粉末劑20mg，確認：認可於小於10歲的兒童的投予量係以認可於10歲以上兒童與成人的投予量的有效成分量40mg(顯示呈無水物之重量)之半量的有效成分量20mg(顯示呈無水物之重量)顯示流行性感冒病毒感染症之治療效果。 Regarding the commercially available Inavir inhalation powder 20 mg, it is confirmed that the dosage approved for the administration of children under 10 years old is 40 mg of the active ingredient approved for the administration dosage for children over 10 years old and adults (shown as anhydrous weight) The half amount of the active ingredient amount of 20 mg (shown as anhydrous weight) shows the therapeutic effect of influenza virus infection.
如試驗例10所示，於成人，可期待以噴霧器用組成物(有效成分160mg)，吸入粉末劑(有效成分40mg)之對A型及B型流行性感冒病毒感染症的治療‧預防效果。 As shown in Test Example 10, in adults, the composition for nebulizer (active ingredient 160 mg) and inhalation powder (active ingredient 40 mg) can be expected to have therapeutic and preventive effects on type A and type B influenza virus infections.
據此，於噴霧器用組成物，亦認為以於10歲以上之兒童及成人被期待有效性的有效性分量160mg之半量的有效成分量80mg有顯示有效性的可能性。 Accordingly, the composition for a nebulizer is also considered to have a possibility of showing effectiveness at a dose of 80 mg, which is half of the effective dose of 160 mg, which is expected to be effective for children over 10 years old and adults.
又，如試驗例10所示，於日本人健康成人男性，因未觀察到至有效性分量320mg之投予量上成為安全性上問題的見解，故即使於小於10歲的兒童，可期待於有效成分量80~320mg顯示有效性。 In addition, as shown in Test Example 10, in Japanese healthy adult males, since the view that the dose of effective dose of 320 mg becomes a safety problem has not been observed, even in children younger than 10 years old, it can be expected in 80~320mg of active ingredients show effectiveness.
關於高齡者，與成人相比，於換氣功能上未觀察到大的差異。據此，暗示針對於日本人健康成人男 性可期待治療‧預防效果的噴霧器用組成物(有效成分80~320mg)，於高齡者亦有顯示治療‧預防效果的可能性。 Regarding the elderly, no major difference was observed in the ventilation function compared with adults. Accordingly, it is suggested to target healthy adult male Japanese The composition for nebulizer (80~320 mg of active ingredient) that can expect therapeutic and preventive effects may show therapeutic and preventive effects even in the elderly.
(試驗例13)成人患者對象之治療效果之研討試驗 (Test Example 13) Research test of therapeutic effect on adult patients
以成人及10歲以上之兒童之A型或B型流行性感冒病毒感染症患者為對象，實施將安慰劑作為對照藥的單盲檢比較試驗。噴霧器用組成物之有效成分量係作成160mg。 A single-blind comparison test using a placebo as a control drug was carried out for adults and children over 10 years of age with influenza A or B influenza virus infection. The active ingredient amount of the composition for nebulizer was 160 mg.
治療用途之有效性係將流行性感冒罹病時間，亦即，自投藥結束時刻，至流行性感冒症狀全部消失，或變成輕度，將該等為持續21.5小時以上之最初時點的時間作為主要的評價項目。 The effectiveness of the therapeutic use is the time from the onset of influenza, that is, from the end of administration until the symptoms of influenza disappear or become mild, and the time from the initial point of lasting more than 21.5 hours is the main factor. Evaluation project.
(試驗例14)兒童患者對象之治療效果之研討試驗 (Test Example 14) Research test on the therapeutic effect of child patients
實施以小於10歲之流行性感冒病毒感染症患者作為對象的非對照非盲檢試驗。噴霧器用組成物之有效成分量係作成160mg。 An uncontrolled, non-blind test was carried out on patients with influenza virus infection younger than 10 years old. The active ingredient amount of the composition for nebulizer was 160 mg.
治療用途之有效性係將流行性感冒罹病時間作為主要的評價項目，亦即，將自投藥結束時刻，至流行性感冒症狀全部消失、或變成輕度，該等持續21.5小時以上之最初時點的時間作為主要的評價項目。 The effectiveness of the therapeutic use is based on the time of influenza attack as the main evaluation item, that is, from the end of administration until the symptoms of influenza are completely disappeared or become mild, and these last for more than 21.5 hours at the initial point of time. Time is the main evaluation item.
Claims (23)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015154754 | 2015-08-05 | ||
| JP2015-154754 | 2015-08-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201717936A TW201717936A (en) | 2017-06-01 |
| TWI762449B true TWI762449B (en) | 2022-05-01 |
Family
ID=57943114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW105124890A TWI762449B (en) | 2015-08-05 | 2016-08-05 | Composition for nebulizer |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP6908523B2 (en) |
| KR (1) | KR20180030399A (en) |
| CN (1) | CN107847482A (en) |
| HK (1) | HK1252798A1 (en) |
| TW (1) | TWI762449B (en) |
| WO (1) | WO2017022814A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109771398B (en) * | 2019-02-25 | 2019-09-20 | 广州南鑫药业有限公司 | A kind of Peramivir solution-type inhalant and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040247628A1 (en) * | 2001-10-24 | 2004-12-09 | Frank-Christophe Lintz | Kit for the preparation of a pharmaceutical composition |
| US20070117783A1 (en) * | 2003-12-16 | 2007-05-24 | Altana Pharma Ag | Aqueous suspensions of ciclesonide for nebulisation |
| CN102264365A (en) * | 2008-12-24 | 2011-11-30 | 第一三共株式会社 | Dry powder pharmaceutical composition for inhalation |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001252578A1 (en) * | 2000-04-25 | 2001-11-07 | Sankyo Company Limited | Preventives for influenza |
| GB0014869D0 (en) * | 2000-06-16 | 2000-08-09 | Glaxo Group Ltd | Novel pharmaceutical formulation |
| ITMI20051999A1 (en) * | 2005-10-21 | 2007-04-22 | Eratech S R L | INHALATION FORMULATIONS OF DRUGS IN DRY POWDER FOR ADMINISTRATION AS SUCH OR WITH NEBULIZER AND EQUIPPED WITH HIGH EROGABILITY RESPIRABILITY AND STABILITY |
| US20080000473A1 (en) * | 2005-12-29 | 2008-01-03 | Hugo Stephenson | pH-Based Methods and Devices for Preventing Hemagglutinin Cell Membrane Fusion |
| US20080063722A1 (en) * | 2006-09-08 | 2008-03-13 | Advanced Inhalation Research, Inc. | Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI) |
| GB0806873D0 (en) * | 2008-04-16 | 2008-05-21 | Breath Ltd | Steroid nebuliser formulation |
| CN101773491A (en) * | 2010-03-23 | 2010-07-14 | 江苏先声药物研究有限公司 | Zanamivir inhalation solution and application thereof |
-
2016
- 2016-08-04 WO PCT/JP2016/072885 patent/WO2017022814A1/en active Application Filing
- 2016-08-04 CN CN201680045861.9A patent/CN107847482A/en active Pending
- 2016-08-04 KR KR1020177029766A patent/KR20180030399A/en not_active Application Discontinuation
- 2016-08-04 JP JP2017533115A patent/JP6908523B2/en active Active
- 2016-08-05 TW TW105124890A patent/TWI762449B/en active
-
2018
- 2018-09-20 HK HK18112099.5A patent/HK1252798A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040247628A1 (en) * | 2001-10-24 | 2004-12-09 | Frank-Christophe Lintz | Kit for the preparation of a pharmaceutical composition |
| US20070117783A1 (en) * | 2003-12-16 | 2007-05-24 | Altana Pharma Ag | Aqueous suspensions of ciclesonide for nebulisation |
| CN102264365A (en) * | 2008-12-24 | 2011-11-30 | 第一三共株式会社 | Dry powder pharmaceutical composition for inhalation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107847482A (en) | 2018-03-27 |
| JPWO2017022814A1 (en) | 2018-05-31 |
| TW201717936A (en) | 2017-06-01 |
| KR20180030399A (en) | 2018-03-22 |
| WO2017022814A1 (en) | 2017-02-09 |
| HK1252798A1 (en) | 2019-06-06 |
| JP6908523B2 (en) | 2021-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1991201B1 (en) | Nebulised antibiotics for inhalation therapy | |
| RU2363449C2 (en) | Aqueous aerosol preparation | |
| ES2332290T3 (en) | PHARMACEUTICAL FORMULATIONS THAT INCLUDE A BETA2 AGONIST OF LONG-TERM ACTION FOR ADMINISTRATION THROUGH NEBULIZATION. | |
| JP2008513444A (en) | Methods for targeted delivery of lidocaine and other local anesthetics and treatment of cough and cough attacks | |
| JP2017528479A (en) | Liquid inhalation formulation containing RPL554 | |
| BR112013029803B1 (en) | DRY POWDER VANCOMICINE COMPOSITIONS | |
| JP2011173929A (en) | Treatment of respiratory bacterial disease | |
| JP2023517532A (en) | Treatment with powdered intranasal epinephrine | |
| CN114652704A (en) | Tryprostinil soft mist inhalant | |
| WO2022170027A1 (en) | Inhaled ivermectin | |
| TWI762449B (en) | Composition for nebulizer | |
| CA2813750A1 (en) | Method for treating cystic fibrosis with inhaled denufosol | |
| JP2024502990A (en) | Inhalable imatinib formulation | |
| JP2024501372A (en) | Pharmaceutical composition for inhalation | |
| Balducci et al. | Drug delivery strategies for pulmonary administration of antibiotics | |
| TWI332403B (en) | ||
| US20230372345A1 (en) | Inhaled PDE-V Inhibitor Drugs | |
| WO2022162635A1 (en) | Novel antiviral compositions and their use in therapy and in the treatment of viral infections | |
| WO2006095788A1 (en) | Particle and preparation containing the particle | |
| CN116897045A (en) | Inhalable imatinib formulations | |
| JP2023550463A (en) | Imatinib formulation, its manufacture and use | |
| JP2023524064A (en) | Clofazimine compositions and methods for treating or preventing viral infections | |
| WO2013005020A1 (en) | Method of producing a nebuliser composition | |
| CN114129546A (en) | Medicinal composition for inhalation | |
| BR112020015646A2 (en) | INTRANASAL EPINEPHRINE FORMULATIONS AND METHODS FOR THE TREATMENT OF DISEASE |