JP2024178478A - Pharmaceuticals - Google Patents
Pharmaceuticals Download PDFInfo
- Publication number
- JP2024178478A JP2024178478A JP2021180616A JP2021180616A JP2024178478A JP 2024178478 A JP2024178478 A JP 2024178478A JP 2021180616 A JP2021180616 A JP 2021180616A JP 2021180616 A JP2021180616 A JP 2021180616A JP 2024178478 A JP2024178478 A JP 2024178478A
- Authority
- JP
- Japan
- Prior art keywords
- capsule
- cepharanthin
- particle size
- packaging
- capsules
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
【課題】ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の予防及び／又は治療のための新たな医薬を提供すること。
【解決手段】（ａ）平均粒子径０．５～１０μｍのセファランチン粉末及び（ｂ）平均粒子径１～２００μｍの乳糖を含有するカプセル剤を気密包装体に収容してなる医薬品であって、当該気密包装体内には不活性ガス及び／又は脱酸素剤が封入されてなる医薬品。
【選択図】なし
The present invention provides a new pharmaceutical agent for the prevention and/or treatment of COVID-19, a disease caused by SARS-CoV-2 infection.
[Solution] A pharmaceutical product comprising a capsule containing (a) cepharanthine powder having an average particle size of 0.5 to 10 μm and (b) lactose having an average particle size of 1 to 200 μm, housed in an airtight package, wherein an inert gas and/or an oxygen scavenger is enclosed within the airtight package.
[Selection diagram] None
Description
本発明は、セファランチンを含有する医薬品に関する。 The present invention relates to a pharmaceutical product containing cepharanthine.
ＣＯＶＩＤ－１９（日本名：新型コロナウイルス感染症）は、２０１９新型コロナウイルス（ＳＡＲＳ－ＣｏＶ－２）によって発症する感染症である。ＣＯＶＩＤ－１９は、２０１９年１１月に中華人民共和国の武漢で発生が確認され、同年１２月にＷＨＯに報告された感染症であり、これ以降世界的に感染が拡大している。その症状は、発熱、空咳、疲労、喀痰、息切れ、咽頭痛、頭痛、筋肉痛、関節痛、嗅覚異常、味覚異常などから始まり、重症例では肺炎が重症化して呼吸不全に陥り、死亡の転帰をとるものである。
その感染力、罹患した際の重症化率等未だ不明な点があることに加え、新型であることから有効な治療法も未だ模索中であり、世界中の人々を不安に陥らせている。
これまでに、多数の既存薬物のスクリーニングがなされ、最近になって、セファランチンがＣＯＶＩＤ－１９の治療薬として期待されている（非特許文献１）。
COVID-19 (Japanese name: novel coronavirus disease) is an infectious disease caused by the 2019 novel coronavirus (SARS-CoV-2). COVID-19 was confirmed to have occurred in Wuhan, People's Republic of China in November 2019 and reported to the WHO in December of the same year, and has since spread worldwide. Symptoms include fever, dry cough, fatigue, phlegm, shortness of breath, sore throat, headache, muscle pain, joint pain, abnormal smell, and abnormal taste, and in severe cases, pneumonia worsens, leading to respiratory failure and death.
There are still many unknowns about the virus, such as its infectiousness and the rate at which it becomes severe when contracted. In addition, because it is a new type of virus, effective treatments are still being sought, causing anxiety around the world.
To date, many existing drugs have been screened, and recently, cepharanthine has been shown to be a promising treatment for COVID-19 (Non-Patent Document 1).
本発明の課題は、ＳＡＲＳ－ＣｏＶ－２感染に基づく疾患、ＣＯＶＩＤ－１９の予防及び／又は治療のための新たな医薬を提供することにある。 The objective of the present invention is to provide a new medicine for the prevention and/or treatment of COVID-19, a disease caused by SARS-CoV-2 infection.
前記セファランチンは、現在、散剤及び錠剤の経口投与用製剤、並びに注射剤が用いられている。本発明者らは、ＳＡＲＳ－ＣｏＶ－２の感染抑制に効果的な薬物として考えられるセファランチンを最もＳＡＲＳ－ＣｏＶ－２が感染する部位に適用することを着想した。その結果、セファランチンを下気道に直接適用できる吸入剤とすることにより、当該目的が達成できることを見出し、また、セファランチンの粒子径を０．５～１０μｍとすることにより、下気道に直接セファランチンを効率よく供給可能な吸入剤が得られることを見出した。そして、さらに検討した結果、粒子径０．５～１０μｍのセファランチンと粒子径１～２００μｍの乳糖をカプセルに封入し、当該カプセルをさらに不活性ガス及び／又は脱酸素剤を封入した気密包装体に収容すれば、保存安定性に優れた、セファランチン含有カプセル剤を含む医薬品が得られることを見出し、本発明を完成した。 Cepharanthin is currently used in the form of powder and tablet preparations for oral administration, as well as in the form of injections. The inventors came up with the idea of applying cepharanthin, which is considered to be an effective drug for suppressing SARS-CoV-2 infection, to the site most likely to be infected by SARS-CoV-2. As a result, they found that the above object can be achieved by making cepharanthin into an inhalant that can be applied directly to the lower respiratory tract, and also found that an inhalant that can efficiently supply cepharanthin directly to the lower respiratory tract can be obtained by making cepharanthin have a particle size of 0.5 to 10 μm. As a result of further investigation, they found that a pharmaceutical containing a capsule containing cepharanthin with excellent storage stability can be obtained by encapsulating cepharanthin with a particle size of 0.5 to 10 μm and lactose with a particle size of 1 to 200 μm and further storing the capsule in an airtight package containing an inert gas and/or an oxygen scavenger, and thus completed the present invention.
すなわち、本発明は、次の発明［１］～［６］を提供するものである。
［１］（ａ）平均粒子径０．５～１０μｍのセファランチン及び（ｂ）平均粒子径１～２００μｍの乳糖を含有するカプセル剤を気密包装体に収容してなる医薬品であって、当該気密包装体内には不活性ガス及び／又は脱酸素剤が封入されてなる医薬品。
［２］カプセル剤中の成分（ａ）と成分（ｂ）の含有質量比（ａ／ｂ）が、０．００１～０．５である［１］記載の医薬品。
［３］カプセル剤が、吸入粉末用カプセル剤である［１］又は［２］記載の医薬品。
［４］１カプセル中の成分（ａ）の含有量が、０．０１～４０ｍｇである［１］～［３］のいずれかに記載の医薬品。
［５］カプセル剤中の成分（ｂ）が乳糖水和物である［１］～［４］のいずれかに記載の医薬品。
［６］不活性ガスが、窒素、ヘリウム、アルゴン、ネオン、クリプトン、ラドン、キセノン及び二酸化炭素から選ばれるガスである［１］～［５］のいずれかに記載の医薬品。
That is, the present invention provides the following inventions [1] to [6].
[1] A pharmaceutical product comprising a capsule containing (a) cepharanthin having an average particle size of 0.5 to 10 μm and (b) lactose having an average particle size of 1 to 200 μm, contained in an airtight package, wherein an inert gas and/or an oxygen scavenger is enclosed in the airtight package.
[2] The pharmaceutical according to [1], wherein the mass ratio (a/b) of the components (a) and (b) in the capsule is 0.001 to 0.5.
[3] The pharmaceutical according to [1] or [2], wherein the capsule is a capsule for powder inhalation.
[4] The pharmaceutical according to any one of [1] to [3], wherein the content of component (a) in one capsule is 0.01 to 40 mg.
[5] The pharmaceutical according to any one of [1] to [4], wherein the component (b) in the capsule is lactose hydrate.
[6] The pharmaceutical agent according to any one of [1] to [5], wherein the inert gas is a gas selected from nitrogen, helium, argon, neon, krypton, radon, xenon and carbon dioxide.
本発明の医薬品は、セファランチン微細粉末と乳糖を含有するカプセルが不活性ガス又は脱酸素剤が封入された気密包装体に収容されており、セファランチンの保存安定性に優れ、吸入粉末剤として使用すると、下気道にセファランチンを効率よく供給可能である。 The pharmaceutical product of the present invention is a capsule containing fine cepharanthine powder and lactose housed in an airtight package filled with an inert gas or oxygen scavenger, and has excellent storage stability for cepharanthine. When used as an inhalation powder, cepharanthine can be efficiently delivered to the lower respiratory tract.
本発明の医薬品の気密包装体に収容されてなるカプセル剤は、（ａ）粒子径０．５～１０μｍのセファランチン及び（ｂ）粒子径１～２００μｍの乳糖を含有する。 The capsules contained in the airtight packaging of the pharmaceutical of the present invention contain (a) cepharanthine having a particle size of 0.5 to 10 μm and (b) lactose having a particle size of 1 to 200 μm.
本発明で用いる成分（ａ）のセファランチンは、化学名を６'，１２'－Ｄｉｍｅｔｈｏｘｙ－２，２'－ｄｉｍｅｔｈｙｌ－６，７－［ｍｅｔｈｙｌｅｎｅｂｉｓ（ｏｘｙ）］ｏｘｙａｃａｎｔｈａｎとする化学物質であり、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されうるアルカロイドの一種である。
セファランチンは、放射線による白血球減少症、円形脱毛症・粃糠性脱毛症、滲出性中耳炎、マムシ咬傷の治療に用いられている。本発明のようにセファランチンを吸入剤とした場合には、これらの適応症に加えて、ＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び／又は治療薬として特に有用である。
Cepharanthine, component (a) used in the present invention, is a chemical substance with the chemical name 6',12'-Dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan, and is a type of alkaloid that can be extracted from Cepharantha gracilis, Cepharantha quinata, Cepharantha japonica, etc.
Cepharanthin is used to treat radiation-induced leukopenia, alopecia areata/alopecia pityriasis, serous otitis media, and viper bites. When cepharanthin is made into an inhalant as in the present invention, in addition to these indications, it is particularly useful as an infection suppressant for SARS-CoV-2 and a preventive and/or therapeutic agent for COVID-19.
本発明において、セファランチンは化学合成されたものでも、タマサキツヅラフジ、コウトウツズラフジ、ハスノハカズラ等から抽出されたものでもいずれをも用いることができる。タマサキツヅラフジより抽出される場合は、セファランチンに加えて、イソテトランドリン、シクレアニン、ベルバミン等のセファランチン以外の他のアルカロイドをも含むタマサキツヅラフジ抽出物を用いることも可能である。セファランチンやタマサキツヅラフジ抽出物は市販品があり、購入して用いることが可能であり、また、タマサキツヅラフジ抽出物は公知の手法を用いることにより、タマサキツヅラフジから製造することができる。 In the present invention, cepharanthine can be either chemically synthesized or extracted from Cepharantha nigricans, Cepharantha quinata, Cepharantha japonica, etc. When extracted from Cepharantha nigricans, it is also possible to use Cepharantha nigricans extracts that contain, in addition to cepharantha, other alkaloids other than cepharantha, such as isotetrandrine, cyclaine, and berbamine. Cepharantha and Cepharantha nigricans extracts are commercially available and can be purchased for use, and Cepharantha nigricans extracts can be produced from Cepharantha nigricans using known methods.
本発明で用いるセファランチンを下気道（気管、気管支、肺臓）に適用するには、セファランチンの下気道への到達性の観点から、その粒子径を０．５～１０μｍとするのが好ましく、１～８μｍとするのがより好ましく、２～８μｍとするのが更に好ましい。粒子径は、レーザー回折散乱式粒度分布測定法（Ｐａｒｔｉｃａ ＬＡ－９５０Ｖ２：株式会社堀場製作所）により得られた累積頻度５０％径を意味する（以下、Ｄ５０と記載する場合がある）。この粒子径は、製造時の粉砕、篩過などによって調整することができる。 When applying the cepharanthin used in the present invention to the lower respiratory tract (trachea, bronchi, lungs), from the viewpoint of the reach of cepharanthin to the lower respiratory tract, the particle size is preferably 0.5 to 10 μm, more preferably 1 to 8 μm, and even more preferably 2 to 8 μm. The particle size refers to the cumulative frequency 50% diameter obtained by a laser diffraction scattering particle size distribution measurement method (Partica LA-950V2: Horiba, Ltd.) (hereinafter, sometimes referred to as D50). This particle size can be adjusted by crushing, sieving, etc. during production.
１カプセル中のセファランチンの含有量は、１回投与量であるのが好ましく、０．０１～４０ｍｇであるのが好ましく、０．１～３０ｍｇであるのがより好ましく、１～２０ｍｇであるのが更に好ましい。
カプセルは、1日につき１～３回程度に分けて、食前、食間、食後、就寝前等に１～８カプセル（好ましくは１～４カプセル、特に好ましくは１～２カプセル）服用することができる。
The content of cepharanthin in one capsule is the amount for one dose, and is preferably 0.01 to 40 mg, more preferably 0.1 to 30 mg, and even more preferably 1 to 20 mg.
The capsules can be taken 1 to 3 times a day, 1 to 8 capsules (preferably 1 to 4 capsules, and particularly preferably 1 to 2 capsules) before meals, between meals, after meals, before going to bed, etc.
本発明で用いる成分（ｂ）の乳糖は、賦形剤である。乳糖としては、乳糖水和物を用いるのが好ましい。
乳糖の粒子径は、セファランチンの下気道への到達性と保存安定性を考慮すると、１～２００μｍであるのが好ましく、１～１８０μｍであるのがより好ましい。この粒子径は、製造時の粉砕、篩過などによって調整することができる。
The lactose of component (b) used in the present invention is an excipient. As the lactose, lactose hydrate is preferably used.
Considering the ability of cepharanthin to reach the lower respiratory tract and storage stability, the particle size of lactose is preferably 1 to 200 μm, more preferably 1 to 180 μm. This particle size can be adjusted by pulverization, sieving, etc. during production.
また、乳糖は、（ｂ１）粒子径１～５０μｍの微細乳糖と（ｂ２）粒子径５０～２００μｍの乳糖とを混合して用いるのが、セファランチンの下気道への到達性と保存安定性の観点でより好ましい。ここで、微細乳糖の粒子径は、１～４０μｍが好ましく、１～３０μｍがより好ましく、１～２０μｍが更に好ましい。粒子径５０～２００μｍの乳糖の粒子径は、７０～１８０μｍが好ましく、８０～１６０μｍがより好ましく、１００～１５０μｍが更に好ましい。また、微細乳糖と粒子径５０～２００μｍの乳糖との含有質量比（ｂ１／ｂ２）は、０．０００１～０．５が好ましく、０．００１～０．２がより好ましく、０．０１～０．１が更に好ましい。 In addition, it is more preferable to use a mixture of (b1) fine lactose having a particle size of 1 to 50 μm and (b2) lactose having a particle size of 50 to 200 μm in terms of the ability of cepharanthin to reach the lower respiratory tract and storage stability. Here, the particle size of the fine lactose is preferably 1 to 40 μm, more preferably 1 to 30 μm, and even more preferably 1 to 20 μm. The particle size of the lactose having a particle size of 50 to 200 μm is preferably 70 to 180 μm, more preferably 80 to 160 μm, and even more preferably 100 to 150 μm. In addition, the mass content ratio (b1/b2) of the fine lactose to the lactose having a particle size of 50 to 200 μm is preferably 0.0001 to 0.5, more preferably 0.001 to 0.2, and even more preferably 0.01 to 0.1.
成分（ａ）と成分（ｂ）の含有質量比（ａ／ｂ）は、セファランチンの下気道への到達性、保存安定性及び粉末吸入の容易性などの観点から、０．００１～０．５が好ましく、０．００５～０．２５がより好ましく、０．０１～０．１が更に好ましい。 The mass ratio (a/b) of component (a) to component (b) is preferably 0.001 to 0.5, more preferably 0.005 to 0.25, and even more preferably 0.01 to 0.1, from the viewpoints of the ability of cepharanthin to reach the lower respiratory tract, storage stability, and ease of powder inhalation.
本発明に用いられるカプセル剤には、前記成分（ａ）及び成分（ｂ）以外に、酢酸、リン酸、ホウ酸、クエン酸、酒石酸、乳酸、アスパラギン酸、ヒスチジン、アルギニン、リジン、グリシン、グルタミン酸、ε－アミノカプロン酸、硫酸及びそれらの薬学的に許容される塩、水酸化ナトリウム、塩酸等のｐＨ調整剤、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル等のパラベン類、ベンザルコニウム塩化物、またはクロロブタノール等の防腐剤、クロモグリク酸ナトリウム等の安定剤、カアトレジン、フェノール等の保存剤、亜硫酸水素ナトリウム、エデト酸ナトリウム、塩化ナトリウム、カルメロースナトリウム、キシリトール、グリセリン、クレアチニン、ステアリン酸マグネシウム、ニコチン酸アミド、マクロゴール（６００、４０００等）、トコフエロール及びその誘導体、亜硝酸ナトリウム、亜硫酸ナトリウム、アスコルビン酸等の安定化剤等、オレイン酸、精製オレイン酸、精製水等の基剤、無水エタノール等の可溶化剤、注射用水等の溶剤等などを含有させることもできるが、それらの含有量はカプセル内容物全量に対し、５質量％以下とするのが好ましく、３質量％以下とするのがより好ましく、２質量％以下とするのが更に好ましい。 In addition to the above-mentioned components (a) and (b), the capsule formulation used in the present invention may contain, in addition to the above-mentioned components (a) and (b), acetic acid, phosphoric acid, boric acid, citric acid, tartaric acid, lactic acid, aspartic acid, histidine, arginine, lysine, glycine, glutamic acid, ε-aminocaproic acid, sulfuric acid and pharma- ceutically acceptable salts thereof, pH adjusters such as sodium hydroxide and hydrochloric acid, parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate, preservatives such as benzalkonium chloride or chlorobutanol, stabilizers such as sodium cromoglycate, preservatives such as carthregin and phenol, sodium bisulfite, sodium edetate, It is also possible to contain stabilizers such as sodium chloride, carmellose sodium, xylitol, glycerin, creatinine, magnesium stearate, nicotinamide, macrogol (600, 4000, etc.), tocopherol and its derivatives, sodium nitrite, sodium sulfite, ascorbic acid, etc., bases such as oleic acid, purified oleic acid, purified water, etc., solubilizers such as absolute ethanol, solvents such as water for injection, etc., but the content of these is preferably 5% by mass or less, more preferably 3% by mass or less, and even more preferably 2% by mass or less of the total amount of the capsule contents.
本発明のカプセル剤は、硬カプセルであるのが好ましく、その剤皮としては、ゼラチン、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール共重合体、プルランなどが挙げられ、安定性の観点からヒドロキシプロピルメチルセルロースが特に好ましい。市販品としては、例えば、ＰＥＧ（マクロゴール）を配合した日本薬局方ゼラチンカプセル（クオリカプス株式会社）、ヒドロキシプロピルメチルセルロースを基剤とするクオリーＶTM（クオリカプス株式会社）やＶｃａｐｓTMＰｌｕｓ（ロンザジャパン株式会社）、ポリビニルアルコール共重合体を基剤とするＰＯＮＤＡＣTMカプセル（日新化成株式会社）、プルランを基剤とするＮＰｃａｐｓTM（ロンザジャパン株式会社）等が挙げられる。 The capsule of the present invention is preferably a hard capsule, and its shell may be gelatin, hydroxypropylmethylcellulose, polyvinyl alcohol copolymer, pullulan, etc., and hydroxypropylmethylcellulose is particularly preferred from the viewpoint of stability. Commercially available products include, for example, Japanese Pharmacopoeia gelatin capsules containing PEG (macrogol) (Qualicaps Co., Ltd.), hydroxypropylmethylcellulose-based Qualy V ™ (Qualicaps Co., Ltd.) and Vcaps ™ Plus (Lonza Japan Co., Ltd.), polyvinyl alcohol copolymer-based PONDAC ™ capsules (Nissin Chemical Industry Co., Ltd.), and pullulan-based NPcaps ™ (Lonza Japan Co., Ltd.).
本発明のカプセル剤は、経口投与剤として使用することもできるが、吸入粉末カプセル剤として使用するのが、セファランチンを下気道に到達させる観点から好ましい。本発明のカプセル剤の使用に際しては、吸入投与のために適切な器具又は装置を使用すればよい。 The capsule of the present invention can be used as an oral administration agent, but is preferably used as an inhalable powder capsule from the viewpoint of allowing cepharanthine to reach the lower respiratory tract. When using the capsule of the present invention, an appropriate tool or device for inhalation administration may be used.
吸入粉末カプセル剤の吸入投与のための器具の具体例としては、ドライパウダー吸入器（Ｄｒｙ Ｐｏｗｄｅｒ Ｉｎｈａｌｅｒ；以下、ＤＰＩと略する）を挙げることができる。本発明の吸入粉末用カプセル剤に用いるデバイスはＤＰＩとして通常用いられるものを使用することができる。例えばデバイスとして、モノヘラー、ハンディヘラー、ブリーズヘラー、フローキャプス等が挙げられる。 Specific examples of devices for inhalation administration of the powdered inhalation capsule include dry powder inhalers (hereinafter abbreviated as DPI). Devices used for the powdered inhalation capsule of the present invention may be those commonly used as DPIs. Examples of such devices include Monohaler, Handihaler, Breezhaler, and Flowcaps.
前記カプセル剤は、さらに、不活性ガス及び／又は脱酸素剤が封入された気密包装体に収容して医薬品として供給する。
本発明において「気密包装体」とは、通常の取扱い、運搬又は保存等の状態において、固体及び液体の包装体外からの実質的な侵入を抑制し得る包装を意味し、第十八改正日本薬局方 通則に定義される「気密容器」及び「密封容器」を包含する概念である。当該包装体としては、定形、不定形のいずれのものも用いることができ、具体的には例えば、ビン包装、ＳＰ（Ｓｔｒｉｐ Ｐａｃｋａｇｅ）包装、ＰＴＰ（Ｐｒｅｓｓ Ｔｈｒｏｕｇｈ Ｐａｃｋａｇｅ）包装、ピロー包装、スティック包装等が挙げられる。本発明においては、さらにこれらを複数組み合わせたものであってもよく、具体的には例えば、前記カプセル剤をまずＰＴＰ包装にて包装し、これをさらにピロー包装にて包装する形態が挙げられる。
The capsules are further supplied as medicines in airtight packaging containing an inert gas and/or an oxygen scavenger.
In the present invention, the term "airtight package" refers to a package that can prevent substantial intrusion of solids and liquids from the outside of the package under normal handling, transportation, storage, etc., and is a concept that includes "airtight container" and "sealed container" defined in the 18th revised Japanese Pharmacopoeia General Rules. The package may be of either a fixed or irregular shape, and specific examples include bottle packaging, SP (Strip Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, etc. In the present invention, a combination of these may also be used, and specific examples include a form in which the capsule is first packaged in a PTP package and then packaged in a pillow package.
気密包装体の包装材料（素材）としては、通常防湿性を発揮し得るものであれば特に限定されず、医薬品や食品の分野で、水分に弱い内容物の防湿等を目的として用いられる材料を適宜用いることができる。
ビン包装に用いられるビン本体の材料としては例えば、ガラス、プラスチック（ポリエステル、ポリエチレン（低密度（ＬＤＰＥ）、高密度（ＨＤＰＥ）を含む）、ポリカーボネート、ポリスチレン、ポリプロピレン等）、金属（アルミニウム）等が挙げられる。また、栓や蓋の材料としては例えば、プラスチック（ポリエステル、ポリエチレン、ポリカーボネート、ポリスチレン、ポリプロピレン等）、金属（アルミニウム）等が挙げられる。ビン包装するに際しては、例えば、前記カプセル剤を、市販のビン内に適当な数量格納し、次いで、適当な栓や蓋で封をすればよい。なお、ビンは、格納するカプセル剤の数量に応じた大きさのものを適宜選択すればよく、ビンの容量としては、例えば、１０～５００ｍＬ程度であり、１４～４００ｍＬが好ましく、２４～３５０ｍＬがより好ましい。ビン包装の材料としては、ポリエチレン、ポリプロピレンが好ましく、低密度ポリエチレン（ＬＤＰＥ）、高密度ポリエチレン（ＨＤＰＥ）がより好ましく、高密度ポリエチレン（ＨＤＰＥ）が特に好ましい。
The packaging material (raw material) for the airtight packaging body is not particularly limited as long as it can normally exhibit moisture-proofing properties, and materials used in the pharmaceutical and food fields for the purpose of moisture-proofing contents that are sensitive to moisture can be used as appropriate.
Examples of materials for the bottle body used in bottle packaging include glass, plastics (polyester, polyethylene (including low density (LDPE) and high density (HDPE)), polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), etc. Examples of materials for the stopper and lid include plastics (polyester, polyethylene, polycarbonate, polystyrene, polypropylene, etc.), metals (aluminum), etc. When packaging in a bottle, for example, a suitable number of the capsules are stored in a commercially available bottle, and then the bottle is sealed with a suitable stopper or lid. Note that the size of the bottle may be appropriately selected according to the number of capsules to be stored, and the capacity of the bottle is, for example, about 10 to 500 mL, preferably 14 to 400 mL, and more preferably 24 to 350 mL. Examples of materials for the bottle packaging are polyethylene and polypropylene, more preferably low density polyethylene (LDPE) and high density polyethylene (HDPE), and particularly preferably high density polyethylene (HDPE).
また、ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装等に用いられる包装材料としては例えば、二軸延伸ポリプロピレン（ＯＰＰ）、二軸延伸ポリエステル（ＰＥＴ）、グルコース変性ＰＥＴ（ＰＥＴ－Ｇ）、二軸延伸ナイロン（ＯＮｙ、ＰＡ）、セロハン、紙、低密度ポリエチレン（ＬＤＰＥ）、直鎖状低密度ポリエチレン（Ｌ－ＬＤＰＥ）、エチレン－酢酸ビニル共重合体（ＥＶＡ）、無延伸ポリプロピレン（ＣＰＰ、ＩＰＰ）、アイオノマー樹脂（ＩＯ）、エチレン－メタクリル酸共重合体（ＥＭＡＡ）、ポリアクリロニトリル（ＰＡＮ）、二軸延伸ポリ塩化ビニリデン（ＰＶＤＣ）、エチレン－ビニルアルコール共重合樹脂（ＥＶＯＨ）、ポリ塩化ビニル（ＰＶＣ）、環状ポリオレフィン（ＣＯＣ）、無延伸ナイロン（ＣＮｙ）、ポリカーボネート（ＰＣ）、ポリスチレン（ＰＳ）、硬質塩化ビニル（ＶＳＣ）等の樹脂や、アルミニウム箔（ＡＬ）のような金属箔等が挙げられ、これらの２種以上を適宜組み合わせた多層構造としてもよい。斯かる多層構造としては例えば、ＰＶＣとＰＶＤＣを積層したもの（ＰＶＣ／ＰＶＤＣ。以下、同様に省略して表記する。）、ＰＶＣ／ＰＶＤＣ／ＰＥ／ＰＶＣ、ＰＶＣ／ＰＶＤＣ／ＰＥ／ＰＶＤＣ／ＰＶＣ、ＣＰＰ／ＣＯＣ／ＣＰＰ、ＰＶＣ／ＡＬ、ＣＰＰ／ＡＬ、ＣＰＰ／ＣＰＰ／ＣＰＰ等が挙げられる。斯かる多層構造を形成する方法としては、押出しラミネート、ドライラミネート、共押出しラミネート、サーマルラミネート、ウェットラミネート、ノンソルベントラミネート、ヒートラミネート等の公知のラミネート方法が挙げられる。ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装等に用いられる包装材料としては、ポリ塩化ビニル、アルミニウム箔が好ましい。 In addition, packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. include, for example, biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose modified PET (PET-G), biaxially oriented nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unoriented polypropylene (CPP, IPP), ionomer resin (IO), ethylene Examples of the resin include ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially oriented polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC), cyclic polyolefin (COC), non-oriented nylon (CNy), polycarbonate (PC), polystyrene (PS), rigid polyvinyl chloride (VSC), and metal foil such as aluminum foil (AL). A multilayer structure may be formed by appropriately combining two or more of these. Examples of such a multilayer structure include a laminate of PVC and PVDC (PVC/PVDC, hereinafter abbreviated as above), PVC/PVDC/PE/PVC, PVC/PVDC/PE/PVDC/PVC, CPP/COC/CPP, PVC/AL, CPP/AL, CPP/CPP/CPP, and the like. Methods for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. Packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, etc. are preferably polyvinyl chloride and aluminum foil.
ＰＴＰ包装の形態としては、公知の方法で樹脂シート等に所望数成形したポケットに、前記カプセル剤を１個又は１投与単位ずつ格納し、次いでアルミニウム箔等の金属箔を構成材料とするシートをフタ材として用いて蓋をすることが挙げられる。なお、ポケットを形成するシートとしてもアルミニウム箔を構成材料とするシートを用いた、いわゆる両面アルミＰＴＰ包装としてもよい。本発明においては、防湿性を高める観点から、ＰＴＰアルミニウム箔を構成材料とするシート等を用いて、カプセル剤を１個又は１投与単位ずつ包装することが挙げられる。本発明においては、アルミニウム箔を構成材料とするシートを用いるのが好ましい。 The form of PTP packaging can be such that the capsules are stored one by one or one dosage unit in a pocket formed in a desired number of pockets in a resin sheet or the like by a known method, and then the pockets are covered with a sheet made of a metal foil such as aluminum foil. The sheet used to form the pockets can also be a so-called double-sided aluminum PTP package, in which a sheet made of aluminum foil is used as the constituent material. In the present invention, from the viewpoint of increasing moisture resistance, the capsules can be packaged one by one or one dosage unit in a sheet made of PTP aluminum foil or the like. In the present invention, it is preferable to use a sheet made of aluminum foil.
なお、本発明の医薬品における、カプセル剤の包装体内部での占有率（容積率）は、包装体がビン包装の場合、通常、２５～９０％であり、２８～８０％が好ましく、３０～７０％がより好ましい。また、包装体がＳＰ包装、ＰＴＰ包装、ピロー包装、スティック包装の場合、通常３０～９８％であり、４０～９５％が好ましく、４５～９３％がより好ましく、５０～９０％が特に好ましい。なお、この場合において、占有率とは、包装体内部の容積に対するカプセル剤の占有率を意味するものであり、包装体内部に格納したカプセル剤の破損防止のための詰め物や中栓等は、空間占有率を算出するに際して考慮されるものではない。 In the pharmaceutical product of the present invention, the occupancy rate (volume rate) of the capsules in the packaging is usually 25-90%, preferably 28-80%, and more preferably 30-70%, when the packaging is a bottle. In addition, when the packaging is a SP package, PTP package, pillow package, or stick package, the occupancy rate is usually 30-98%, preferably 40-95%, more preferably 45-93%, and particularly preferably 50-90%. In this case, the occupancy rate means the occupancy rate of the capsules relative to the volume inside the package, and fillers and stoppers for preventing damage to the capsules stored inside the package are not taken into consideration when calculating the space occupancy rate.
本発明においては、気密包装体として市販の包装体をそのまま用いてもよく、また市販の包装材料を加工して用いてもよい。このような市販品としては例えば、ビン包装の包装体としては、Ｚ－シリーズ（以上、阪神化成工業社製）等が挙げられる。また、ＳＰ包装、ＰＴＰ包装、ピロー包装やスティック包装用の包装材料としては、スミライトＶＳＳ、スミライトＶＳＬ、スミライトＮＳ、スミライトＦＣＬ（以上、住友ベークライト社製）、ＴＡＳシリーズ（大成化工社製）、ＰＴＰ用ビニホイル、ＰＴＰ用スーパーホイル（以上、三菱樹脂社製）、ニッパクアルミ箔（日本製箔社製）、アルミ箔銀無地（大和化学工業社製）等が挙げられる。 In the present invention, commercially available packaging materials may be used as airtight packaging materials as they are, or commercially available packaging materials may be processed and used. Examples of such commercially available products include the Z-series bottle packaging materials (all manufactured by Hanshin Chemical Industry Co., Ltd.). Examples of packaging materials for SP packaging, PTP packaging, pillow packaging, and stick packaging include SUMILITE VSS, SUMILITE VSL, SUMILITE NS, and SUMILITE FCL (all manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Taisei Chemical Industry Co., Ltd.), vinyl foil for PTP, super foil for PTP (all manufactured by Mitsubishi Plastics, Inc.), Nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and plain silver aluminum foil (manufactured by Daiwa Chemical Industry Co., Ltd.).
本発明の医薬品において、前記カプセル剤を収容した気密包装体内には不活性ガス及び／又は脱酸素剤が封入される。不活性ガス及び／又は脱酸素剤を封入することにより、カプセル内のセファランチン粉末の保存安定性が向上する。具体的には、セファランチンの類縁物質の生成が抑制される。 In the pharmaceutical product of the present invention, an inert gas and/or an oxygen scavenger is enclosed in the airtight packaging that contains the capsule. By enclosing an inert gas and/or an oxygen scavenger, the storage stability of the cepharanthin powder in the capsule is improved. Specifically, the production of cepharanthin-related substances is suppressed.
不活性ガスとしては、窒素、ヘリウム、アルゴン、ネオン、クリプトン、ラドン、キセノン、二酸化炭素などが挙げられる。このうち、入手容易性、安全性などの点から窒素ガス、アルゴンガス等がより好ましい。不活性ガスの封入は、気密包装体内の空気を不活性ガスに置換することにより、酸素を極力減少させればよい。 Examples of inert gases include nitrogen, helium, argon, neon, krypton, radon, xenon, and carbon dioxide. Of these, nitrogen gas and argon gas are more preferable in terms of availability and safety. The inert gas can be filled by replacing the air in the airtight packaging with the inert gas, thereby reducing oxygen as much as possible.
脱酸素剤としては、鉄粉などの金属粉末、第一鉄塩、亜二チオン酸塩、亜硫酸塩、ハロゲン化金属などの無機物を主体とするもの、アスコルビン酸、エリソルビン酸、それらの塩、ヒドロキノンやカテコールなどのポリフェノールなどの有機化合物を主体とするものなど種々のものが知られており、毒性がなく且つ酸素吸収性能に優れるものであればいずれも使用できる。また、脱酸素剤には自力反応型と水分依存型があるが、本発明ではそれらのいずれも使用できる。市販のものとしては、三菱ガス化学社製の「エージレス」（商品名）のＳタイプ、ＳＳタイプ、Ｚタイプ、ＦＸタイプ、ＺＭタイプ、ＳＡタイプ、ＧＬタイプ、「ファーマキープ」（商品名）などが知られており、エージレスは本発明において好適に使用できる。また、脱酸素剤の市販品としては、大江化学工業社製の「タモツ」（商品名）のＶＸタイプ、Ｄタイプ、「酸素カット」（商品名）のＧＤタイプなども使用できる。
また、脱酸素剤としては、酸素吸収量（脱酸素剤１個当たりの酸素吸収量：ｍL）が１０ｍL以上のものが好ましく、２０ｍL以上のものがより好ましく、２５ｍL以上のものがさらに好ましい。また、脱酸素剤としては、水分活性値（AW）が高い食品の脱酸素剤として用いられるものであるのが好ましく、食品への適用範囲（水分活性値）が、０．３以上のものが好ましい。
Various oxygen scavengers are known, including those based on inorganic substances such as metal powders such as iron powder, ferrous salts, dithionites, sulfites, and metal halides, and those based on organic compounds such as ascorbic acid, erythorbic acid, their salts, and polyphenols such as hydroquinone and catechol. Any of these can be used as long as they are non-toxic and have excellent oxygen absorption performance. There are also self-reacting and moisture-dependent types of oxygen scavengers, and either of these can be used in the present invention. Commercially available oxygen scavengers include S type, SS type, Z type, FX type, ZM type, SA type, and GL type of "Ageless" (trade name) manufactured by Mitsubishi Gas Chemical Co., Ltd., and "PharmaKeep" (trade name), and Ageless can be suitably used in the present invention. Commercially available oxygen scavengers include VX type, D type of "Tamotsu" (trade name) manufactured by Oe Chemical Industry Co., Ltd., and GD type of "Oxygen Cut" (trade name).
The oxygen absorber preferably has an oxygen absorption capacity (oxygen absorption capacity per oxygen absorber: mL) of 10 mL or more, more preferably 20 mL or more, and even more preferably 25 mL or more. The oxygen absorber is preferably used as an oxygen absorber for foods with a high water activity value (AW), and the range of application to foods (water activity value) is preferably 0.3 or more.
本発明においては、例えば、前記カプセル剤をまずＰＴＰ包装にて包装し、これをさらにピロー包装にて包装する形態が挙げられ、このピロー包装とＰＴＰ包装の空間に不活性ガス及び／又は脱酸素剤を封入するのが好ましい。 In the present invention, for example, the capsules may be first packaged in a PTP package, and then further packaged in a pillow package. It is preferable to enclose an inert gas and/or an oxygen scavenger in the space between the pillow package and the PTP package.
本発明の医薬品は、セファランチンの適応症である円形脱毛症・粃糠性脱毛症、滲出性中耳炎、マムシ咬傷に加えて、ＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び／又は治療薬として用いることができる。その投与量は、患者の体重、年齢、性別、症状などによって異なるが、通常は成人に対して、セファランチンとして１日１～２０ｍｇの範囲が挙げられる。また、本発明の医薬品をＳＡＲＳ－ＣｏＶ－２の感染抑制薬、ＣＯＶＩＤ－１９の予防及び/又は治療薬として用いる場合、ネルフィナビルなどの抗ＨＩＶ剤と併用することもできる。 The pharmaceutical of the present invention can be used as an infection suppressant for SARS-CoV-2 and as a preventive and/or therapeutic drug for COVID-19, in addition to the indications for cepharanthin, which are alopecia areata, alopecia pityroides, serous otitis media, and viper bites. The dosage varies depending on the patient's weight, age, sex, symptoms, etc., but typically ranges from 1 to 20 mg of cepharanthin per day for adults. In addition, when the pharmaceutical of the present invention is used as an infection suppressant for SARS-CoV-2 and as a preventive and/or therapeutic drug for COVID-19, it can also be used in combination with an anti-HIV drug such as nelfinavir.
次に実施例を挙げて本発明をさらに詳細に説明するが、本発明は、これら実施例に制限されるものではない。 The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.
参考例１
ジェットミルで粉砕したセファランチン（粒子径：１．２μｍ：レーザー回折法により測定）１．５ｇに乳糖水和物９８．５ｇを添加し、ハイフレックスグラル（深江パウテック（株）製、ＨＦ－ＧＳ－２Ｊ）で混合した。得られた粉末０．１ｇをカプセルに充填して、吸入粉末剤を製造した。
Reference Example 1
98.5 g of lactose hydrate was added to 1.5 g of cepharanthine (particle size: 1.2 μm: measured by laser diffraction method) ground with a jet mill, and mixed with Hyflex Glar (HF-GS-2J, manufactured by Fukae Powtec Co., Ltd.) 0.1 g of the obtained powder was filled into a capsule to produce a powder for inhalation.
参考比較例１
未粉砕のセファランチン（粒子径：５０μｍ：レーザー回折法により測定）１．５ｇに乳糖水和物９８．５ｇを添加し、ハイフレックスグラル（深江パウテック（株）製、ＨＦ－ＧＳ－２Ｊ）で混合した。得られた粉末０．１ｇをカプセルに充填して、吸入粉末剤を製造した。
Reference Comparative Example 1
98.5 g of lactose hydrate was added to 1.5 g of unground cepharanthine (particle size: 50 μm: measured by laser diffraction method), and mixed with Hyflex Glar (HF-GS-2J, manufactured by Fukae Powtec Co., Ltd.) 0.1 g of the obtained powder was filled into a capsule to produce a powder for inhalation.
試験例１
参考例１及び参考比較例１で得た吸入粉末剤について、デバイスとしてモノヘラーを用いて、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）を測定した。結果を表１に示す。
（１）Ｓｔａｇｅ２表示率（％）
吸入剤のＩｎ ｖｉｔｒｏ評価装置であるＴｗｉｎ Ｉｍｐｉｎｇｅｒを用いて、気道到達率であるＳｔａｇｅ２表示率を求めた。
（２）微粒子量（ＦＰＤ）（％）
日本薬局方 第十七改正第二追補の吸入剤の空気力学的粒度測定法に準拠して、装置１のマルチステージリキッドインピンジャーを用いて評価した。
Test Example 1
The Stage 2 display rate (%) and fine particle dose (FPD) (%) were measured using a Monohaler device for the dry powder inhalants obtained in Reference Example 1 and Reference Comparative Example 1. The results are shown in Table 1.
(1) Stage 2 display rate (%)
The Stage 2 display rate, which is the airway reach rate, was determined using Twin Impinger, an in vitro evaluation device for inhalants.
(2) Fine particle amount (FPD) (%)
The evaluation was carried out using the multi-stage liquid impinger device 1 in accordance with the aerodynamic particle size measurement method for inhalants in the Japanese Pharmacopoeia, 17th Edition, Second Supplement.
表１の結果から明らかなように、参考例１の吸入粉末剤は、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）が３０％程度と高く、肺深部までセファランチンを到達させることが可能と考えられた。
一方、参考比較例１のセファランチン未粉砕の場合は、Ｓｔａｇｅ２表示率（％）及び微粒子量（ＦＰＤ）（％）が３％程度と低く、肺深部までセファランチンを到達させることは困難と考えられた。
As is clear from the results in Table 1, the inhalable powder of Reference Example 1 had a high Stage 2 display rate (%) and fine particle dose (FPD) (%) of approximately 30%, indicating that it is possible for cepharanthin to reach the deep lungs.
On the other hand, in the case of unpulverized cepharanthin in Reference Comparative Example 1, the Stage 2 display rate (%) and fine particle dose (FPD) (%) were low at about 3%, suggesting that it would be difficult for cepharanthin to reach the deep lungs.
参考例２
［サンプル１］
セファランチン（Ｄ５０：１３３μｍ）２ｇをガラス瓶（２Ｋ規格瓶）に入れ、サンプル１とした。
［サンプル２］
ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇをガラス瓶（２Ｋ規格瓶）に入れ、サンプル２とした。
［サンプル３］
ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇと乳糖水和物１８ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０）を混合し、ガラス瓶（２Ｋ規格瓶）に入れ、サンプル３とした。
［サンプル４］
ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇと乳糖水和物１８ｇ（Ｄ５０：８．１μｍ、商品名：ＩｎｈａＬａｃTM４００）を混合し、ガラス瓶（２Ｋ規格瓶）に入れ、サンプル４とした。
Reference Example 2
[Sample 1]
2 g of cepharanthin (D50: 133 μm) was placed in a glass bottle (standard 2K bottle) to prepare Sample 1.
[Sample 2]
2 g of cepharanthin (D50: 3.5 μm) pulverized by a jet mill was placed in a glass bottle (standard 2K bottle) to prepare sample 2.
[Sample 3]
2 g of cepharanthin (D50: 3.5 μm) ground with a jet mill and 18 g of lactose hydrate (D50: 134 μm, product name: InhaLac ™ 120) were mixed and placed in a glass bottle (standard 2K bottle) to prepare sample 3.
[Sample 4]
2 g of cepharanthin (D50: 3.5 μm) ground with a jet mill and 18 g of lactose hydrate (D50: 8.1 μm, product name: InhaLac ™ 400) were mixed and placed in a glass bottle (standard 2K bottle) to prepare sample 4.
試験例２
上記各種サンプルにつき、保存開始前及び８０℃３日間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣ装置を用いて測定した。具体的には、セファランチンの類縁物質の割合を、セファランチン及びその類縁物質に由来する総ピーク面積に対する面積百分率（％）として測定した。
そして、得られた各種サンプルについての保存開始前及び８０℃３日間保存後のセファランチンの類縁物質の割合（％）より、以下の式に従い、各種サンプルについてのセファランチン由来の分解物の増加率（％）を算出した。
セファランチン由来の分解物の増加率（％）＝（８０℃３日間保存後のセファランチンの類縁物質の割合（％））－（保存開始前のセファランチンの類縁物質の割合（％））
Test Example 2
The ratio of decomposition products (related substances) derived from cepharanthin in each of the above samples was measured using an HPLC device before the start of storage and after storage at 80° C. for 3 days. Specifically, the ratio of the related substances of cepharanthin was measured as an area percentage (%) relative to the total peak area derived from cepharanthin and its related substances.
Then, from the percentages (%) of cepharanthin-related substances in each sample obtained before the start of storage and after storage at 80°C for 3 days, the increase rate (%) of cepharanthin-derived decomposition products in each sample was calculated according to the following formula.
Increase rate (%) of decomposition products derived from cepharanthin=(Ratio (%) of cepharanthin-related substances after storage at 80°C for 3 days)-(Ratio (%) of cepharanthin-related substances before storage)
＜分解物の測定＞
分解物の測定は、以下の条件にて液体クロマトグラフ法により定量した。
検出器：紫外吸光光度計（測定波長：２８４ｎｍ）
カラム温度：４０℃付近の一定温度
カラム：液体クロマトグラフ用オクタデシルシリル化シリカゲル（４．６ｍｍ×１５ｃｍ、φ５μｍ）
移動相：アセトニトリル／薄めたトリエチルアミン（１→２０００）混液（１：１）
<Measurement of decomposition products>
The amount of decomposition products was determined by liquid chromatography under the following conditions.
Detector: ultraviolet spectrophotometer (measurement wavelength: 284 nm)
Column temperature: constant temperature around 40°C Column: octadecylsilylated silica gel for liquid chromatography (4.6 mm x 15 cm, φ5 μm)
Mobile phase: Acetonitrile/diluted triethylamine (1→2000) mixture (1:1)
得られた結果を表２に示す。
表２より、セファランチンは、微粉末とすることにより、保存安定性が低下することが判明した。セファランチンは、乳糖と混合しても、保存安定性が低下した。
The results obtained are shown in Table 2.
From Table 2, it was found that the storage stability of cepharanthin was reduced by making it into a fine powder. The storage stability of cepharanthin was also reduced when it was mixed with lactose.
製造例１
ジェットミルで粉砕したセファランチン（Ｄ５０：３．５μｍ）２ｇ、乳糖水和物１７．２６ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）、及び乳糖水和物０．７４ｇ（Ｄ５０：８．１μｍ、商品名：ＩｎｈａＬａｃTM４００、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を混合し、粉末を得た。
Production Example 1
2 g of cepharanthine (D50: 3.5 μm) ground using a jet mill, 17.26 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sold by: MEGGLE GmbH & CO.KG), and 0.74 g of lactose hydrate (D50: 8.1 μm, trade name: InhaLac ™ 400, sold by: MEGGLE GmbH & CO.KG) were mixed to obtain a powder.
実施例１
製造例１で得た粉末を１カプセル当たり１００ｍｇとなるように３号ＨＰＭＣカプセル（商品名：ＶｃａｐｓTMＰｌｕｓ（白色）、販売会社：ロンザジャパン株式会社）に充填し２００カプセル調製した。
得られた５カプセルをガラス瓶（２Ｋ規格瓶）に入れ、医薬製剤を製した。
Example 1
The powder obtained in Production Example 1 was filled into No. 3 HPMC capsules (product name: Vcaps ™ Plus (white), sold by Lonza Japan Co., Ltd.) so that each capsule contained 100 mg of the powder, to prepare 200 capsules.
The obtained 5 capsules were placed in a glass bottle (standard 2K bottle) to prepare a pharmaceutical preparation.
比較例１
製造例１で得た粉末１００ｍｇをガラス瓶（２Ｋ規格瓶）に入れ、医薬製剤を製した。
Comparative Example 1
100 mg of the powder obtained in Preparation Example 1 was placed in a glass bottle (standard 2K bottle) to prepare a pharmaceutical preparation.
試験例３
上記各種サンプルにつき、保存開始前及び６０℃２週間保存後のセファランチン由来の類縁物質の割合を、ＨＰＬＣ装置を用いて測定した。
Test Example 3
The proportion of cepharanthine-derived analogues in each of the above samples was measured using an HPLC device before and after storage at 60° C. for 2 weeks.
表３より、（ａ）平均粒子径０．５～１０μｍのセファランチンと、（ｂ）平均粒子径１～２００μｍの乳糖とを、カプセル中に封入することにより、保存安定性が向上することがわかった。 From Table 3, it was found that storage stability was improved by encapsulating (a) cepharanthine with an average particle size of 0.5 to 10 μm and (b) lactose with an average particle size of 1 to 200 μm in a capsule.
実施例２
前記実施例１で得た５カプセルをガラス瓶（７Ｋ規格瓶）に入れ、ガラス瓶中の空気を窒素に置換し医薬品を製した。
Example 2
The five capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle), and the air in the glass bottle was replaced with nitrogen to prepare a pharmaceutical product.
実施例３
前記実施例１で得た５カプセル及び脱酸素剤１個（１２．７ｇ）（三菱ガス化学株式会社製：商品名 エージレスＳＳ－３００）をガラス瓶（７Ｋ規格瓶）に入れ、医薬品を製した。
Example 3
The five capsules obtained in Example 1 and one oxygen absorber (12.7 g) (product name Ageless SS-300, manufactured by Mitsubishi Gas Chemical Co., Ltd.) were placed in a glass bottle (7K standard bottle) to prepare a medicine.
比較例２
前記実施例１で得た５カプセルをガラス瓶（７Ｋ規格瓶）に入れ、医薬品を製した。
Comparative Example 2
The five capsules obtained in Example 1 were placed in a glass bottle (7K standard bottle) to prepare a pharmaceutical product.
試験例４
前記実施例２，３及び比較例２の各サンプルにつき、保存開始前及び６０℃４週間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣ装置を用いて測定した。
その結果、表４に示すように、カプセル剤を収容した気密包装体の内部に窒素ガス又は脱酸素剤を封入することにより、セファランチン微粉末由来の類縁物質の生成量が減少し、セファランチンの安定性が保持できることがわかる。
Test Example 4
For each sample of Examples 2 and 3 and Comparative Example 2, the proportion of decomposition products (related substances) derived from cepharanthin was measured using an HPLC device before the start of storage and after storage at 60° C. for 4 weeks.
As a result, as shown in Table 4, by sealing nitrogen gas or an oxygen scavenger inside the airtight packaging containing the capsules, the amount of related substances produced from cepharanthin fine powder is reduced, and the stability of cepharanthin can be maintained.
実施例４
前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＳ－１２０２、材質：ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（１．３ｇ）（三菱ガス化学株式会社製：商品名 エージレスＳＳ-３０）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。
Example 4
The capsules obtained in Example 1 were packed in a press-through pack (molded sheet, manufactured by Sumitomo Bakelite Co., Ltd., product name: SUMILITE ™ VSS-1202, material: PVC; aluminum foil, manufactured by Toyo Aluminum K.K., product name: Plain PTP (PVC color)), and the resulting preparation was packaged in an aluminum bag (manufactured by Seisan Nippon Sha: AL-E) together with one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Company, Inc.: product name: AGELESS SS-30).
実施例５
前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＳ－１２０２、材質：ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（０．９ｇ）（三菱ガス化学株式会社製：商品名 エージレスＦＸ-３０）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。
Example 5
The capsules obtained in Example 1 were packed in a press-through pack (molded sheet, manufactured by Sumitomo Bakelite Co., Ltd., product name: SUMILITE ™ VSS-1202, material: PVC; aluminum foil, manufactured by Toyo Aluminum K.K., product name: Plain press-through pack (PVC color)), and the resulting preparation was packaged in an aluminum bag (manufactured by Seisan Nippon Sha: AL-E) together with one oxygen absorber (0.9 g) (manufactured by Mitsubishi Gas Chemical Company, Inc.: product name: Ageless FX-30).
実施例６
前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＮＳ－３４５０、材質：ＣＰＰ、アルミ箔…東洋アルミニウム株式会社製、商品名：ＰＴＰ ＡＬ ＣＰＰヨウ ムジ）包装した製剤を脱酸素剤１個（１．５ｇ）（三菱ガス化学株式会社製：商品名 エージレスＺＭ-１）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。
Example 6
The capsules obtained in Example 1 were packaged in a PTP (molded sheet...manufactured by Sumitomo Bakelite Co., Ltd., product name: SUMILITE ™ NS-3450, material: CPP, aluminum foil...manufactured by Toyo Aluminum K.K., product name: PTP AL CPP Yodo Plain), and the preparation was packaged in an aluminum bag (manufactured by Seisan Nippon Sha: AL-E) together with one oxygen absorber (1.5 g) (manufactured by Mitsubishi Gas Chemical Company, Inc.: product name Ageless ZM-1).
実施例７
前記実施例１で得たカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＶＳＬ－４６０３、材質：ＰＶＣ／ＰＥ／ＰＶＤＣ／ＰＶＣ、アルミ箔…東洋アルミニウム株式会社製、商品名：ムジＰＴＰ（ＰＶＣヨウ））包装した製剤を脱酸素剤１個（１．３ｇ）（三菱ガス化学株式会社製：商品名 エージレスＺ－３０ＰＫＣ）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）に包装した。
Example 7
The capsules obtained in Example 1 were packaged in a press-through pack (molded sheet: Sumitomo Bakelite Co., Ltd., product name: SUMILITE ™ VSL-4603, material: PVC/PE/PVDC/PVC; aluminum foil: Toyo Aluminum K.K., product name: Plain PTP (PVC)), and the resulting preparation was packaged in an aluminum bag (manufactured by Seisan Nippon Sha: AL-E) together with one oxygen absorber (1.3 g) (manufactured by Mitsubishi Gas Chemical Co., Inc.: product name: Ageless Z-30PKC).
試験例５
前記実施例４～７の各サンプルにつき、保存開始前及び８０℃３日間保存後のセファランチン由来の分解物（類縁物質）の割合を、ＨＰＬＣを用いて測定した。
その結果、表５に示すように、カプセル剤を収容した気密包装体の内部に窒素ガス又は脱酸素剤を封入することにより、セファランチン微粉末由来の類縁物質の生成量が減少し、セファランチンの安定性が保持できることがわかる。
なお、用いた脱酸素剤のタイプ、酸素吸収量及び適用範囲を表６に示す。表６中、酸素吸収量は脱酸素剤１個当たりの酸素吸収量（２５度）を示し、適用範囲は好ましい水分活性（ＡＷ）の範囲を示す。表６より、脱酸素剤のタイプは本発明の効果に影響しないことがわかる。
Test Example 5
For each of the samples of Examples 4 to 7, the proportion of decomposition products (related substances) derived from cepharanthin was measured by HPLC before the start of storage and after storage at 80° C. for 3 days.
As a result, as shown in Table 5, by sealing nitrogen gas or an oxygen scavenger inside the airtight packaging containing the capsules, the amount of related substances produced from cepharanthin fine powder is reduced, and the stability of cepharanthin can be maintained.
The type, oxygen absorption amount, and application range of the oxygen absorbers used are shown in Table 6. In Table 6, the oxygen absorption amount indicates the oxygen absorption amount per oxygen absorber (25 degrees), and the application range indicates the preferred water activity (AW) range. It can be seen from Table 6 that the type of oxygen absorber does not affect the effect of the present invention.
ＰＶＣ：ポリ塩化ビニル
ＣＰＰ：無延伸ポリプロピレン
ＰＶＤＣ：ポリ塩化ビニリデン
ＰＥ：ポリエチレン
PVC: Polyvinyl chloride CPP: Non-oriented polypropylene PVDC: Polyvinylidene chloride PE: Polyethylene
製造例２
ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品４．０ｇと乳糖水和物１６．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を混合し、粉末を得た。
Production Example 2
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sold by: MEGGLE GmbH & CO.KG) were pulverized in a jet mill to obtain a pulverized product (average particle size: 2.6 μm). 4.0 g of the pulverized product was mixed with 16.0 g of lactose hydrate (D50: 134 μm, trade name: InhaLac ™ 120, sold by: MEGGLE GmbH & CO.KG) to obtain a powder.
製造例３
ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品２．０ｇと乳糖水和物１８．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を混合し、粉末を得た。
Production Example 3
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac ™ 120, sold by MEGGLE GmbH & CO.KG) were pulverized in a jet mill to obtain a pulverized product (average particle size: 2.6 μm). 2.0 g of the pulverized product was mixed with 18.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac ™ 120, sold by MEGGLE GmbH & CO.KG) to obtain a powder.
製造例４
ジェットミルでセファランチン（Ｄ５０：１３３μｍ）５．０ｇと乳糖水和物５．０ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を粉砕し、粉砕品を得た（平均粒子径：２．６μｍ）。得られた粉砕品０．４ｇと乳糖水和物１９．６ｇ（Ｄ５０：１３４μｍ、商品名：ＩｎｈａＬａｃTM１２０、販売会社：ＭＥＧＧＬＥ ＧｍｂＨ＆ ＣＯ.ＫＧ）を混合し、粉末を得た。
Production Example 4
5.0 g of cepharanthine (D50: 133 μm) and 5.0 g of lactose hydrate (D50: 134 μm, product name: InhaLac ™ 120, sold by MEGGLE GmbH & CO.KG) were pulverized in a jet mill to obtain a pulverized product (average particle size: 2.6 μm). 0.4 g of the pulverized product was mixed with 19.6 g of lactose hydrate (D50: 134 μm, product name: InhaLac ™ 120, sold by MEGGLE GmbH & CO.KG) to obtain a powder.
実施例８～１０
前記製造例２～４で得た粉末を１カプセル当たり１００ｍｇとなるように３号ＨＰＭＣカプセル（商品名：ＶｃａｐｓTMＰｌｕｓ（白色）、販売会社：ロンザジャパン株式会社）に充填し２０カプセル調製した。
得られたカプセルをＰＴＰ（成形シート…住友ベークライト株式会社製、商品名：スミライトTMＮＳ－３４５０、材質：ＣＰＰ、アルミ箔…東洋アルミニウム株式会社製、商品名：ＰＴＰ ＡＬ ＣＰＰヨウ ムジ）包装した製剤（２個×５個カプセルを1シートとし、2シート）を脱酸素剤１個（１．５ｇ）（三菱ガス化学株式会社製：商品名 エージレスＺＭ-１）と共にアルミ袋（株式会社生産日本社製：ＡＬ－Ｅ）（１６ｃｍ×１０ｃｍ）に包装し、実施例８～１０とした。
Examples 8 to 10
The powders obtained in the above Production Examples 2 to 4 were filled into No. 3 HPMC capsules (product name: Vcaps ™ Plus (white), sold by Lonza Japan Co., Ltd.) so that each capsule contained 100 mg of the powder, to prepare 20 capsules.
The obtained capsules were packaged in a press-through pack (molded sheet...manufactured by Sumitomo Bakelite Co., Ltd., product name: SUMILITE ™ NS-3450, material: CPP; aluminum foil...manufactured by Toyo Aluminum K.K., product name: PTP AL CPP Yomuji), and the resulting preparation (2 sheets, each sheet containing 2 capsules x 5 capsules) was packaged in an aluminum bag (manufactured by Seisan Nippon Sha: AL-E) (16 cm x 10 cm) together with one oxygen absorber (1.5 g) (manufactured by Mitsubishi Gas Chemical Company, Inc.: product name Ageless ZM-1), to give Examples 8 to 10.
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