JPWO2004087146A1 - Method for producing fine particle mixture - Google Patents
Method for producing fine particle mixture Download PDFInfo
- Publication number
- JPWO2004087146A1 JPWO2004087146A1 JP2005504255A JP2005504255A JPWO2004087146A1 JP WO2004087146 A1 JPWO2004087146 A1 JP WO2004087146A1 JP 2005504255 A JP2005504255 A JP 2005504255A JP 2005504255 A JP2005504255 A JP 2005504255A JP WO2004087146 A1 JPWO2004087146 A1 JP WO2004087146A1
- Authority
- JP
- Japan
- Prior art keywords
- fine particle
- particle mixture
- preparation
- carrier particles
- inhalation
- 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.)
- Withdrawn
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
- A61K9/0012—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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本発明により、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩を含有する微粒子混合物を高収率で製造する製造方法、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩を含有する吸入用製剤を高品質で製造する製造方法等が提供される。また、有効成分の微粒子と、担体粒子および補助物質を含有する吸入用製剤を製造する際に、有効成分の微粒子の担体粒子への付着率を上昇させる方法が提供される。According to the invention, 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4-methoxy-spiro [1,3-benzodioxole-2,1′-cyclopentane] or 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4-methoxy-, a production method for producing a fine particle mixture containing a pharmacologically acceptable salt thereof in high yield A production method for producing a high-quality preparation for inhalation containing spiro [1,3-benzodioxole-2,1'-cyclopentane] or a pharmacologically acceptable salt thereof is provided. Also provided is a method for increasing the adhesion rate of active ingredient microparticles to carrier particles in the preparation of an inhalation preparation containing active ingredient microparticles, carrier particles and auxiliary substances.
Description
本発明は、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩を含有する微粒子混合物の製造方法、該製造方法によって得られる微粒子混合物、およびこれを含有する吸入用製剤等に関する。 The present invention relates to 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4-methoxy-spiro [1,3-benzodioxole-2,1′-cyclopentane] or The present invention relates to a method for producing a fine particle mixture containing a pharmacologically acceptable salt, a fine particle mixture obtained by the production method, an inhalation preparation containing the same, and the like.
従来、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩をホスホジエステラーゼＩＶ阻害剤として用いることが知られている（国際公開第９６／３６６２４号パンフレット参照）。
一方、ドライパウダー吸入用製剤に含まれる有効成分は、肺や気管支等の疾患部位に到達させ吸収させるために、微細な粒子（微粒子）であることが必要とされている（インターナショナル・ジャーナル・オブ・ファーマコロジー（Ｉｎｔ．Ｊ．Ｐｈａｒｍ．）、１９９４年、第１０１巻、１頁）。通常このような微粒子は、有効成分の粉砕によって得られる。しかし微粒子は凝集しやすい性質をもつため、微粒子を吸入用製剤に用いた場合、例えば吸入器からの十分な有効成分排出量が得られない、口腔内や上気道で有効成分が凝集してしまい肺や気管支への有効成分の到達率が低い等の問題がある。このため、吸入用製剤では、粉砕した有効成分と担体粒子を混合し、担体粒子表面に粉砕した有効成分を付着させることによってその凝集を防止し、肺や気管支等の疾患部位への有効成分の到達率を向上させる手法が知られている。しかしながら、有効成分の微粒子を担体粒子に付着させた場合、付着力が強すぎると有効成分は吸入操作中に担体粒子から分離せず、口腔、咽喉に沈着してしまい期待された薬効を発揮することができない。特に有効成分の含量が低いと、有効成分の微粒子が担体粒子から再分散されにくくなり、結果として疾患部位への有効成分の到達量が低下する等の問題が生じる。
そこで、かかる問題を解決するために、有効成分の微粒子を担体粒子に付着させた吸入用製剤であって、吸入器からの十分な有効成分排出量が得られ、かつ吸入後に有効成分が担体粒子から良好に分離する吸入用製剤について報告がされている（特表平８−５０１０５６公報、特開２００１−１５１６７３号公報参照）。特表平８−５０１０５６公報では、有効成分の微粒子と、補助物質からなる吸入用製剤が報告され、特開２００１−１５１６７３号公報は、有効成分と、担体粒子および補助物質からなる吸入用製剤の製造方法であって、有効成分と補助物質を混合して粉砕することにより、有効成分と補助物質の微粒子混合物を製造する工程を含む製造方法を報告している。
一方、有効成分の微粒子を製造する工程においては、該微粒子が粉砕装置に付着してしまいその損失を生じる等の問題が生じている。また、有効成分の微粒子を担体粒子に付着させる場合、有効成分の担体粒子への付着力が、有効成分の混合容器への付着力と比較して小さいと、有効成分の微粒子と担体粒子を混合する工程において、有効成分が混合容器に付着してしまいその損失を生じる等の問題が生じている。粉砕によって得られる微粒子では、粉砕していない粒子と比較して付着性、帯電性等が増大することが知られており（ファーマシューティカル・テクノロジー（Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ）、１９９４年、第１８巻、５８頁）、このことは、有効成分の微粒子を製造する際に、収率が低下する原因の１つとなっている。また、有効成分の微粒子を担体粒子に付着させた吸入用製剤を製造する際に、有効成分の担体粒子への付着率が低下し、品質が低下する原因の１つとなっている。Conventionally, 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4-methoxy-spiro [1,3-benzodioxole-2,1′-cyclopentane] or a drug thereof It is known to use physically acceptable salts as phosphodiesterase IV inhibitors (see WO 96/36624).
On the other hand, the active ingredient contained in the dry powder inhalation preparation is required to be fine particles (fine particles) in order to reach and absorb diseased parts such as the lungs and bronchi (International Journal of Pharmacology (Int. J. Pharm.), 1994, Vol. 101, page 1). Such fine particles are usually obtained by grinding active ingredients. However, since fine particles tend to aggregate, when the fine particles are used in an inhalation formulation, for example, the active ingredient cannot be sufficiently discharged from the inhaler, and the active ingredient aggregates in the oral cavity and upper respiratory tract. There are problems such as low reach of active ingredients to the lungs and bronchi. For this reason, in inhalation preparations, the pulverized active ingredient and carrier particles are mixed, and the pulverized active ingredient is adhered to the surface of the carrier particles to prevent the aggregation, and the active ingredient to the diseased part such as lung and bronchus is prevented. A technique for improving the reach is known. However, when the fine particles of the active ingredient are adhered to the carrier particles, if the adhesive force is too strong, the active ingredient does not separate from the carrier particles during the inhalation operation, and is deposited in the oral cavity and throat, thereby exhibiting the expected medicinal effect. I can't. In particular, when the content of the active ingredient is low, the fine particles of the active ingredient are hardly redispersed from the carrier particles, resulting in problems such as a reduction in the amount of the active ingredient that reaches the diseased site.
Accordingly, in order to solve such a problem, a preparation for inhalation in which fine particles of an active ingredient are attached to carrier particles, a sufficient amount of the active ingredient discharged from the inhaler can be obtained, and the active ingredient becomes carrier particles after inhalation. Have been reported on a preparation for inhalation that is well separated from urine (see JP-T-8-501056 and JP-A-2001-151673). JP-A-8-501056 reports an inhalation preparation comprising fine particles of an active ingredient and an auxiliary substance, and JP-A-2001-151673 discloses an inhalation preparation comprising an active ingredient, carrier particles and an auxiliary substance. A manufacturing method is reported which includes a step of producing a fine particle mixture of an active ingredient and an auxiliary substance by mixing and pulverizing the active ingredient and the auxiliary substance.
On the other hand, in the process of producing fine particles of the active ingredient, there are problems such as the fine particles adhering to the pulverizer and loss thereof. In addition, when the active ingredient fine particles are adhered to the carrier particles, the active ingredient fine particles and the carrier particles are mixed if the adhesion force of the active ingredient to the carrier particles is smaller than the adhesion force of the active ingredient to the mixing container. In the process, the active ingredient adheres to the mixing container, causing problems such as loss. It is known that fine particles obtained by pulverization have increased adhesion, chargeability and the like as compared with non-pulverized particles (Pharmaceutical Technology, 1994, Vol. 18, 58). This is one of the causes of a decrease in yield when producing fine particles of the active ingredient. In addition, when manufacturing an inhalation preparation in which fine particles of the active ingredient are adhered to the carrier particles, the adhesion rate of the active ingredient to the carrier particles is reduced, which is one of the causes of quality deterioration.
本発明の目的は、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩を含有する微粒子混合物を高収率で製造する製造方法、７−［２−（３，５−ジクロロ−４−ピリジル）−１−オキソエチル］−４−メトキシ−スピロ［１，３−ベンゾジオキソール−２，１’−シクロペンタン］またはその薬理学的に許容される塩を含む吸入用製剤を高品質で製造する製造方法等を提供することにある。
本発明は、以下の（１）〜（２９）に関する。
（１）式（Ｉ）
（２）補助物質が糖類または糖アルコール類である前記（１）記載の製造方法。
（３）補助物質が乳糖である前記（１）記載の製造方法。
（４）微粒子混合物の平均粒子径が１０μｍ以下である前記（１）〜（３）のいずれかに記載の製造方法。
（５）微粒子混合物の平均粒子径が１〜６μｍである前記（１）〜（３）のいずれかに記載の製造方法。
（６）化合物（Ｉ）またはその薬理学的に許容される塩と補助物質とを混合し、得られた混合物を混合粉砕する工程を含むことを特徴とする化合物（Ｉ）またはその薬理学的に許容される塩を含有する吸入用製剤の製造方法。
（７）補助物質が糖類または糖アルコール類である前記（６）記載の製造方法。
（８）補助物質が乳糖である前記（６）記載の製造方法。
（９）微粒子混合物の平均粒子径が１０μｍ以下である前記（６）〜（８）のいずれかに記載の製造方法。
（１０）微粒子混合物の平均粒子径が１〜６μｍである前記（６）〜（８）のいずれかに記載の製造方法。
（１１）化合物（Ｉ）またはその薬理学的に許容される塩と補助物質を含有する微粒子混合物。
（１２）補助物質が糖類または糖アルコール類である前記（１１）記載の微粒子混合物。
（１３）補助物質が乳糖である（１１）記載の微粒子混合物。
（１４）微粒子混合物の平均粒子径が１０μｍ以下である前記（１１）〜（１３）のいずれかに記載の微粒子混合物。
（１５）微粒子混合物の平均粒子径が１〜６μｍである前記（１１）〜（１３）のいずれかに記載の微粒子混合物。
（１６）前記（１）〜（５）のいずれかに記載の製造方法によって得られる化合物（Ｉ）またはその薬理学的に許容される塩を含有する微粒子混合物。
（１７）前記（１１）〜（１６）のいずれかに記載の微粒子混合物を含有する吸入用製剤。
（１８）前記（１１）〜（１６）のいずれかに記載の微粒子混合物と担体粒子を含有する吸入用製剤。
（１９）担体粒子が糖類または糖アルコール類である前記（１８）記載の吸入用製剤。
（２０）担体粒子が乳糖である前記（１８）記載の吸入用製剤。
（２１）補助物質と担体粒子が同一物質である、前記（１８）〜（２０）のいずれかに記載の吸入用製剤。
（２２）担体粒子の平均粒子径が４０〜１２５μｍである前記（１８）〜（２１）のいずれかに記載の吸入用製剤。
（２３）微粒子混合物と担体粒子を重量比で１：１〜１：２０の範囲で含有する前記（１８）〜（２２）のいずれかに記載の吸入用製剤。
（２４）担体粒子に付着した有効成分の微粒子を含有する吸入用製剤の製造工程において、有効成分と補助物質とを混合し、得られた混合物を混合粉砕して微粒子混合物とし、該微粒子混合物と担体粒子を混合することを特徴とする有効成分の微粒子の担体粒子への付着率を上昇させる方法。
（２５）担体粒子が糖類または糖アルコール類である前記（２４）記載の吸入用製剤の有効成分の微粒子の担体粒子への付着率を上昇させる方法。
（２６）担体粒子が乳糖である前記（２４）記載の吸入用製剤の有効成分の微粒子の担体粒子への付着率を上昇させる方法。
（２７）担体粒子の平均粒子径が４０〜１２５μｍである前記（２４）〜（２６）のいずれかに記載の吸入用製剤の有効成分の微粒子の担体粒子への付着率を上昇させる方法。
（２８）微粒子混合物と担体粒子の重量比を１：１〜１：２０の範囲とする前記（２４）〜（２７）のいずれかに記載の吸入用製剤の有効成分の微粒子の担体粒子への付着率を上昇させる方法。
（２９）有効成分が化合物（Ｉ）またはその薬理学的に許容される塩である前記（２４）〜（２８）のいずれかに記載の吸入用製剤の有効成分の微粒子の担体粒子への付着率を上昇させる方法。
化合物（Ｉ）の薬理学的に許容される塩は、薬理学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等を包含する。
化合物（Ｉ）の薬理学的に許容される酸付加塩としては、塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩、酢酸塩、マレイン酸塩、フマル酸塩、クエン酸塩等の有機酸塩があげられ、薬理学的に許容される金属塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等があげられ、薬理学的に許容されるアンモニウム塩としては、アンモニウム、テトラメチルアンモニウム等の塩があげられ、薬理学的に許容される有機アミン付加塩としては、モルホリン、ピペリジン等の付加塩があげられ、薬理学的に許容されるアミノ酸付加塩としては、グリシン、フェニルアラニン、リジン、アスパラギン酸、グルタミン酸等の付加塩があげられる。
補助物質としては、糖類、糖アルコール類等が好ましく、例えば乳糖、Ｄ−マンニトール等があげられる。
担体粒子としては、糖類、糖アルコール類等が好ましく、例えば乳糖、Ｄ−マンニトール等が挙げられる。担体粒子としては、上記の補助物質と同一の物質を用いることが好ましく、例えば担体、補助物質双方に乳糖を用いるのが好ましい。用いられる担体粒子の平均粒子径は特に限定されないが、好ましくは４０〜１２５μｍ、より好ましくは５０〜８０μｍである。
次に、化合物（Ｉ）の製造方法について説明する。
化合物（Ｉ）は、国際公開第９６／３６６２４号パンフレットに記載の方法により製造することができる。
化合物（Ｉ）には、互変異性体等の立体異性体が存在し得るが、本発明の微粒子混合物および吸入用製剤には、これらを含め、全ての可能な異性体およびそれらの混合物を使用することができる。
化合物（Ｉ）の塩を取得したいとき、化合物（Ｉ）が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物（Ｉ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて単離、精製すればよい。
また、化合物（Ｉ）およびその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明の吸入用製剤に使用することができる。
本発明の微粒子混合物の製造方法および本発明の吸入用製剤の製造方法において、化合物（Ｉ）またはその薬理学的に許容される塩と補助物質とを混合し、得られた混合物を混合粉砕する際に用いられる粉砕方法は、当該分野において周知の方法であれば特に限定されないが、例えば乳鉢粉砕、ボールミル粉砕、ハンマーミル粉砕、流体エネルギー粉砕（例えばジェットミル粉砕）等があげられ、通常−３０℃〜５０℃の温度範囲で、好ましくは−２０℃〜４０℃の温度範囲で粉砕される。粉砕は、好ましくは−３０〜１０℃、より好ましくは−２０℃〜５℃の低温下で、および／または例えば窒素、アルゴン等の不活性気体下で行うのが好ましい。これにより、有効成分の品質をよりよく保つことができる。
本発明により製造される微粒子混合物の平均粒子径は、好ましくは１０μｍ以下、より好ましくは１〜６μｍである。
本発明における化合物（Ｉ）またはその薬理学的に許容される塩と補助物質との混合比は、特に限定されないが、好ましくは重量比で１：１〜１：２００、より好ましくは重量比で１：３〜１：１００である。
本発明はまた、例えば上記微粒子混合物の製造方法によって得られる化合物（Ｉ）またはその薬理学的に許容される塩と補助物質とを含有する微粒子混合物をも包含する。
本発明の微粒子混合物は、化合物（Ｉ）またはその薬理学的に許容される塩と補助物質とから製造することができるが、その製造方法は、特に限定されず、例えば各成分を粉砕した後に混合し製造する方法、各成分を混合後粉砕し製造する方法等いずれの方法を用いてもよく、化合物（Ｉ）またはその薬理学的に許容される塩と補助物質を未粉砕の状態で混合した後、混合粉砕する方法が好ましい。混合粉砕を行うことにより、粒子径が微細な、均一性の高い微粒子混合物が得られる。さらに、微粒子の粉砕装置への付着を低減し、回収率を向上させることができる。
用いられる粉砕方法は、当該分野において周知の方法であれば特に限定されないが、例えば乳鉢粉砕、ボールミル粉砕、ハンマーミル粉砕、流体エネルギー粉砕（例えばジェットミル粉砕）等があげられ、通常−３０℃〜５０℃の温度範囲で、好ましくは−２０℃〜４０℃の温度範囲で粉砕される。また、有効成分または有効成分と補助物質との混合物の粉砕は、好ましくは−３０〜１０℃、より好ましくは−２０℃〜５℃の低温下で、および／または例えば窒素、アルゴン等の不活性気体下で行うのが好ましい。これにより、有効成分の品質をよりよく保つことができる。
本発明において製造される微粒子混合物および本発明の微粒子混合物の平均粒子径は、好ましくは１０μｍ以下、より好ましくは１〜６μｍである。
化合物（Ｉ）またはその薬理学的に許容される塩と補助物質との混合比は、特に限定されないが、好ましくは重量比で１：１〜１：２００、より好ましくは重量比で１：３〜１：１００である。
本発明の吸入用製剤は、化合物（Ｉ）またはその薬理学的に許容される塩と補助物質を含有する微粒子混合物を含有する吸入用製剤であって、該微粒子混合物を、担体粒子と混合することにより製造される吸入用製剤を包含する。
化合物（Ｉ）またはその薬理学的に許容される塩と補助物質とを含有する微粒子混合物と上記担体粒子との混合比は特に限定されないが、好ましくは重量比で１：０．１〜１：５０、より好ましくは重量比で１：０．５〜１：２０である。
本発明の吸入用製剤は、活性成分として化合物（Ｉ）またはその薬理学的に許容される塩を単独で、または任意の他の治療のための有効成分との混合物として含有することができる。
また、本発明の吸入用製剤は、例えばドライパウダー吸入器等の吸入器を用いて投与することが可能である。
本発明の有効成分の微粒子の担体粒子への付着率を上昇させる方法は、本発明の吸入用製剤の製造方法において化合物（Ｉ）を有効成分に代えて吸入用製剤を製造することにより行うことができる。本発明の有効成分の微粒子の担体粒子への付着率を上昇させる方法における有効成分としては、原則としては吸入用製剤として使用されるものであれば特に限定されないが、特に粒子同士が凝集しやすいものがあげられ、例えば脂溶性の高い薬物等があげられる。脂溶性の高い薬物としては例えば副腎皮質ホルモン類、性ホルモン類、活性型ビタミンＤ３類、プロスタグランジン類等があげられる。副腎皮質ホルモン類としては、例えばプロピオン酸ベクロメタゾン、酢酸トリアムシノロン、フルニソリド、ブデソニド、プロピオン酸フルチカゾン等があげられ、性ホルモン類としては、例えばテストステロン、エストロジェン、エストラジオール等があげられ、活性型ビタミンＤ３類としては、例えば１α，２４−ジヒドロキシビタミンＤ３、１α，２５−ジヒドロキシビタミンＤ３（カルシフェロール）、カルシポトリオール、１α−ヒドロキシ−２４−オキソビタミンＤ３、１α，２５−ジヒドロキシビタミンＤ３−２６，２３−ラクトン、１α，２５−ジヒドロキシビタミンＤ３−２６，２３−パーオキシラクトン、２６，２６，２６，２７，２７，２７−ヘキサフルオロ−１α，２５−ジヒドロキシビタミンＤ３等があげられ、プロスタグランジン類としては、例えばプロスタグランジンＥ１（アルプロスタジル）、プロスタグランジンＦ２α（ジノプロスト）、プロスタグランジンＩ２（エポプロステノール）、ベラプロスト、クリンプロスト等があげられる。
以下に、本発明の様態を実施例、比較例、および試験例で説明する。The object of the present invention is to provide 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4-methoxy-spiro [1,3-benzodioxole-2,1′-cyclopentane. Or a method for producing a fine particle mixture containing a pharmacologically acceptable salt thereof in high yield, 7- [2- (3,5-dichloro-4-pyridyl) -1-oxoethyl] -4- To provide a production method for producing a high-quality preparation for inhalation containing methoxy-spiro [1,3-benzodioxole-2,1′-cyclopentane] or a pharmacologically acceptable salt thereof. is there.
The present invention relates to the following (1) to (29).
(1) Formula (I)
(2) The production method according to the above (1), wherein the auxiliary substance is a saccharide or a sugar alcohol.
(3) The production method according to the above (1), wherein the auxiliary substance is lactose.
(4) The production method according to any one of (1) to (3), wherein an average particle size of the fine particle mixture is 10 μm or less.
(5) The manufacturing method in any one of said (1)-(3) whose average particle diameter of microparticles | fine-particles mixture is 1-6 micrometers.
(6) Compound (I) or a pharmacological thereof, which comprises a step of mixing Compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance, and mixing and pulverizing the resulting mixture. For producing a preparation for inhalation containing an acceptable salt.
(7) The production method according to the above (6), wherein the auxiliary substance is a saccharide or a sugar alcohol.
(8) The production method according to the above (6), wherein the auxiliary substance is lactose.
(9) The production method according to any one of (6) to (8), wherein an average particle size of the fine particle mixture is 10 μm or less.
(10) The production method according to any one of (6) to (8), wherein the fine particle mixture has an average particle size of 1 to 6 μm.
(11) A fine particle mixture containing compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance.
(12) The fine particle mixture according to the above (11), wherein the auxiliary substance is a saccharide or a sugar alcohol.
(13) The fine particle mixture according to (11), wherein the auxiliary substance is lactose.
(14) The fine particle mixture according to any one of (11) to (13), wherein an average particle size of the fine particle mixture is 10 μm or less.
(15) The fine particle mixture according to any one of (11) to (13), wherein the fine particle mixture has an average particle size of 1 to 6 μm.
(16) A fine particle mixture containing compound (I) obtained by the production method according to any one of (1) to (5) or a pharmacologically acceptable salt thereof.
(17) A preparation for inhalation containing the fine particle mixture according to any one of (11) to (16).
(18) A preparation for inhalation comprising the fine particle mixture according to any one of (11) to (16) and carrier particles.
(19) The preparation for inhalation according to the above (18), wherein the carrier particles are sugars or sugar alcohols.
(20) The preparation for inhalation according to the above (18), wherein the carrier particles are lactose.
(21) The inhalable preparation according to any one of (18) to (20), wherein the auxiliary substance and the carrier particles are the same substance.
(22) The inhalable preparation according to any one of (18) to (21), wherein the carrier particles have an average particle size of 40 to 125 μm.
(23) The inhalable preparation according to any one of (18) to (22), wherein the fine particle mixture and the carrier particles are contained in a weight ratio of 1: 1 to 1:20.
(24) In the production process of the inhalable preparation containing fine particles of the active ingredient attached to the carrier particles, the active ingredient and the auxiliary substance are mixed, and the resulting mixture is mixed and pulverized to obtain a fine particle mixture; A method for increasing the adhesion rate of fine particles of active ingredients to carrier particles, which comprises mixing carrier particles.
(25) A method for increasing the adhesion rate of fine particles of active ingredients of the inhalable preparation according to (24), wherein the carrier particles are sugars or sugar alcohols.
(26) The method for increasing the adhesion rate of fine particles of the active ingredient of the inhalable preparation according to (24), wherein the carrier particles are lactose.
(27) A method for increasing the adhesion rate of fine particles of active ingredients of a preparation for inhalation according to any one of (24) to (26), wherein the average particle diameter of the carrier particles is 40 to 125 μm.
(28) The active ingredient of the inhalation preparation according to any one of (24) to (27), wherein the weight ratio of the fine particle mixture to the carrier particles is in the range of 1: 1 to 1:20; A method to increase the adhesion rate.
(29) Adhesion of fine particles of active ingredients of the inhalation preparation according to any one of (24) to (28), wherein the active ingredient is compound (I) or a pharmacologically acceptable salt thereof to carrier particles How to increase the rate.
The pharmacologically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
Examples of the pharmacologically acceptable acid addition salt of Compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, acetate, maleate, fumarate, citrate, and the like. Examples of the pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like Examples of pharmacologically acceptable ammonium salts include ammonium and tetramethylammonium salts. Examples of pharmacologically acceptable organic amine addition salts include morpholine and piperidine addition salts. Examples of the pharmacologically acceptable amino acid addition salts include addition salts of glycine, phenylalanine, lysine, aspartic acid, glutamic acid and the like.
As the auxiliary substance, saccharides, sugar alcohols and the like are preferable, and examples thereof include lactose and D-mannitol.
As the carrier particles, saccharides, sugar alcohols and the like are preferable, and examples thereof include lactose and D-mannitol. As the carrier particles, it is preferable to use the same substance as the above-mentioned auxiliary substance. For example, it is preferable to use lactose for both the carrier and the auxiliary substance. The average particle size of the carrier particles used is not particularly limited, but is preferably 40 to 125 μm, more preferably 50 to 80 μm.
Next, the manufacturing method of compound (I) is demonstrated.
Compound (I) can be produced by the method described in WO 96/36624.
In compound (I), stereoisomers such as tautomers may exist, but all possible isomers and mixtures thereof are used in the fine particle mixture and inhalation preparation of the present invention. can do.
When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be dissolved or suspended and isolated and purified by adding acid or base.
Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used in the inhalation preparation of the present invention. be able to.
In the method for producing the fine particle mixture of the present invention and the method for producing the inhalable preparation of the present invention, the compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance are mixed, and the resulting mixture is mixed and pulverized. The pulverization method used in the process is not particularly limited as long as it is a method well known in the art, and examples thereof include mortar pulverization, ball mill pulverization, hammer mill pulverization, fluid energy pulverization (for example, jet mill pulverization), and usually -30. It grind | pulverizes in the temperature range of -50 to 40 degreeC, Preferably it is -20 to 40 degreeC. The pulverization is preferably performed at a low temperature of −30 to 10 ° C., more preferably −20 to 5 ° C. and / or an inert gas such as nitrogen or argon. Thereby, the quality of an active ingredient can be kept better.
The average particle size of the fine particle mixture produced according to the present invention is preferably 10 μm or less, more preferably 1 to 6 μm.
The mixing ratio of compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance in the present invention is not particularly limited, but is preferably 1: 1 to 1: 200 by weight, more preferably by weight. 1: 3 to 1: 100.
The present invention also includes a fine particle mixture containing Compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance obtained, for example, by the above method for producing a fine particle mixture.
The fine particle mixture of the present invention can be produced from Compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance, but the production method is not particularly limited. For example, after each component is pulverized Any method may be used, such as a method of mixing and manufacturing, a method of mixing and pulverizing each component, and mixing compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance in an unground state. Then, a method of mixing and pulverizing is preferable. By performing the mixing and pulverization, a fine particle mixture having a fine particle diameter and high uniformity can be obtained. Furthermore, the adhesion of the fine particles to the pulverizer can be reduced and the recovery rate can be improved.
The pulverization method used is not particularly limited as long as it is a method well known in the art, and examples thereof include mortar pulverization, ball mill pulverization, hammer mill pulverization, fluid energy pulverization (for example, jet mill pulverization), and the like. It grind | pulverizes in the temperature range of 50 degreeC, Preferably it is -20 to 40 degreeC. Further, the pulverization of the active ingredient or the mixture of the active ingredient and the auxiliary substance is preferably performed at a low temperature of −30 to 10 ° C., more preferably −20 ° C. to 5 ° C. and / or inert such as nitrogen and argon. It is preferable to carry out under gas. Thereby, the quality of an active ingredient can be kept better.
The average particle size of the fine particle mixture produced in the present invention and the fine particle mixture of the present invention is preferably 10 μm or less, more preferably 1 to 6 μm.
The mixing ratio of compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance is not particularly limited, but is preferably 1: 1 to 1: 200 by weight, more preferably 1: 3 by weight. ~ 1: 100.
The inhalable preparation of the present invention is an inhalable preparation containing a fine particle mixture containing Compound (I) or a pharmaceutically acceptable salt thereof and an auxiliary substance, and the fine particle mixture is mixed with carrier particles. Inhalable preparations.
The mixing ratio of the fine particle mixture containing Compound (I) or a pharmacologically acceptable salt thereof and an auxiliary substance and the carrier particles is not particularly limited, but is preferably 1: 0.1 to 1: 1 by weight. 50, more preferably 1: 0.5 to 1:20 by weight.
The inhalable preparation of the present invention may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other therapeutic active ingredient.
The inhalable preparation of the present invention can be administered using an inhaler such as a dry powder inhaler.
The method for increasing the adhesion rate of the fine particles of the active ingredient of the present invention to the carrier particles is carried out by producing a preparation for inhalation by substituting compound (I) for the active ingredient in the production process for inhalation preparation of the present invention. Can do. The active ingredient in the method for increasing the adhesion rate of the fine particles of the active ingredient to the carrier particles of the present invention is not particularly limited as long as it is used as a preparation for inhalation in principle. Examples thereof include drugs having high fat solubility. Lipophilic high Drugs example adrenocortical hormones, sex hormones, active vitamin D 3 compounds, prostaglandins and the like. Examples of corticosteroids include beclomethasone propionate, triamcinolone acetate, flunisolide, budesonide, fluticasone propionate, and the like. Examples of sex hormones include testosterone, estrogen, and estradiol. Active vitamin D 3 For example, 1α, 24-dihydroxyvitamin D 3 , 1α, 25-dihydroxyvitamin D 3 (calciferol), calcipotriol, 1α-hydroxy-24-oxovitamin D 3 , 1α, 25-dihydroxyvitamin D3-26 , 23-lactone, 1α, 25-dihydroxyvitamin D 3 -26,23-peroxylactone, 26,26,26,27,27,27-hexafluoro-1α, 25-dihydroxyvitamin D 3 and the like. Examples of the prostaglandins include prostaglandin E 1 (alprostadil), prostaglandin F 2 α (dinoprost), prostaglandin I 2 (epoprostenol), beraprost, and climprost.
Below, the aspect of this invention is demonstrated with an Example, a comparative example, and a test example.
化合物（Ｉ）０．５ｇと乳糖２．５ｇを混合後、ジェットミル（Ａ−Ｏ ＪＥＴ；セイシン企業、以下同じ）を用い、室温下、空気圧力５００ｋＰａ、粉末送り速度１ｇ／分で混合粉砕し、微粒子混合物（２．７ｇ、収率９０％）を得た。得られた微粒子混合物（０．１ｇ）と乳糖（Ｐｈａｒｍａｔｏｓｅ ３２５Ｍ；ＤＭＶジャパン、以下同じ）を重量比１：１６の比率で混合し、吸入用製剤を得た。 After mixing 0.5 g of Compound (I) and 2.5 g of lactose, using a jet mill (A-O JET; Seishin Enterprise, the same shall apply hereinafter), mixing and grinding at room temperature, air pressure of 500 kPa, and powder feed rate of 1 g / min A fine particle mixture (2.7 g, yield 90%) was obtained. The obtained fine particle mixture (0.1 g) and lactose (Pharmacatose 325M; DMV Japan, the same applies hereinafter) were mixed at a weight ratio of 1:16 to obtain an inhalation preparation.
化合物（Ｉ）０．５ｇと乳糖２５ｇを混合後、ジェットミルを用い、室温下、空気圧力５００ｋＰａ、粉末送り速度１ｇ／分で混合粉砕し、微粒子混合物（２４．５ｇ、収率９６％）を得た。得られた微粒子混合物（１．０ｇ）と乳糖を重量比１：１の比率で混合し、吸入用製剤を得た。
比較例１
化合物（Ｉ）０．５ｇを、単独でジェットミルを用い、室温下、空気圧力５００ｋＰａ、粉末送り速度０．２ｇ／分で粉砕し、微粒子状粉砕物（０．２４ｇ、収率４８％）を得た。得られた微粒子状粉砕物（０．０２ｇ）と乳糖を重量比１：１０１の比率で混合し、吸入用製剤を得た。
試験例１
実施例１、２および比較例１で得られた、各微粒子混合物および微粒子状粉砕物に含まれる化合物（Ｉ）の平均粒子径を測定した。分散媒に０．１％ラウリル硫酸ナトリウム（ＳＬＳ）水溶液を用いることで微粒子混合物または微粒子状粉砕物中の乳糖を溶解させ、化合物（Ｉ）の平均粒子径を測定した。測定にはレーザー光散乱粒度分布測定装置（ＬＤＳＡ−１３００Ａ；東日アプリケーションズ）を用いた。結果を第１表に示す。
試験例２
実施例１、２および比較例１で得られた各吸入用製剤中の化合物（Ｉ）の含量を測定した。各製剤１０２ｍｇ（理論上化合物（Ｉ）は１ｍｇ含有される）について秤量し、含量を測定した。例数はｎ＝６とした。結果を第２表に示す。
Comparative Example 1
Compound (I) 0.5 g was pulverized alone using a jet mill at room temperature at an air pressure of 500 kPa and a powder feed rate of 0.2 g / min to obtain a finely pulverized product (0.24 g, yield 48%). Obtained. The obtained finely pulverized product (0.02 g) and lactose were mixed at a weight ratio of 1: 101 to obtain an inhalation preparation.
Test example 1
The average particle diameter of the compound (I) contained in each fine particle mixture and finely pulverized product obtained in Examples 1 and 2 and Comparative Example 1 was measured. By using 0.1% sodium lauryl sulfate (SLS) aqueous solution as the dispersion medium, lactose in the fine particle mixture or finely pulverized product was dissolved, and the average particle size of compound (I) was measured. A laser light scattering particle size distribution analyzer (LDSA-1300A; Tohn Applications) was used for the measurement. The results are shown in Table 1.
Test example 2
The content of Compound (I) in each inhalation preparation obtained in Examples 1 and 2 and Comparative Example 1 was measured. 102 mg of each preparation (theoretically containing 1 mg of compound (I)) was weighed and the content was measured. The number of examples was n = 6. The results are shown in Table 2.
本発明により、化合物（Ｉ）またはその薬理学的に許容される塩を含有する微粒子混合物を高収率で製造する製造方法、化合物（Ｉ）またはその薬理学的に許容される塩を含有する吸入用製剤を高品質で製造する製造方法等が提供される。また、有効成分の微粒子と、担体粒子および補助物質を含有する吸入用製剤を製造する際に、有効成分の微粒子の担体粒子への付着率を上昇させる方法が提供される。 According to the present invention, a production method for producing a fine particle mixture containing compound (I) or a pharmacologically acceptable salt thereof in high yield, containing compound (I) or a pharmacologically acceptable salt thereof. A production method for producing a preparation for inhalation with high quality is provided. Also provided is a method for increasing the adhesion rate of active ingredient microparticles to carrier particles in the preparation of an inhalation preparation containing active ingredient microparticles, carrier particles and auxiliary substances.
Claims (29)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003094511 | 2003-03-31 | ||
| JP2003094511 | 2003-03-31 | ||
| PCT/JP2004/004588 WO2004087146A1 (en) | 2003-03-31 | 2004-03-31 | Processes for production of fine particle mixtures |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPWO2004087146A1 true JPWO2004087146A1 (en) | 2006-06-29 |
Family
ID=33127397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005504255A Withdrawn JPWO2004087146A1 (en) | 2003-03-31 | 2004-03-31 | Method for producing fine particle mixture |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPWO2004087146A1 (en) |
| WO (1) | WO2004087146A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101232905B (en) * | 2005-07-25 | 2013-01-09 | 大塚制药株式会社 | Oral preparation useful in measuring capacity to metabolize pyridine |
| CN104737016B (en) | 2012-08-20 | 2017-09-29 | 大塚制药株式会社 | Determine the method for Sugar metabolism ability and the composition for this method |
| ES2754246T3 (en) | 2013-03-15 | 2020-04-16 | Otsuka Pharma Co Ltd | Composition for use in a method of measuring the sugar / fatty acid burn ratio |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9322014D0 (en) * | 1993-10-26 | 1993-12-15 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
| PT771794E (en) * | 1995-05-19 | 2006-09-29 | Kyowa Hakko Kogyo Kk | HETEROCYCLIC COMPOUNDS CONTAINING OXYGEN |
| JP4266399B2 (en) * | 1997-12-04 | 2009-05-20 | 帝人株式会社 | Pharmaceutical composition for inhalation in powder form |
| JP2001072586A (en) * | 1999-09-06 | 2001-03-21 | Nikken Chem Co Ltd | Powdery inhaling preparation and its production |
| JP2001151673A (en) * | 1999-09-06 | 2001-06-05 | Nikken Chem Co Ltd | Production of powdery preparation for inhalation |
| JP4125512B2 (en) * | 2000-11-29 | 2008-07-30 | 伊藤ハム株式会社 | Powder formulation and method for producing the same |
-
2004
- 2004-03-31 WO PCT/JP2004/004588 patent/WO2004087146A1/en active Application Filing
- 2004-03-31 JP JP2005504255A patent/JPWO2004087146A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004087146A1 (en) | 2004-10-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6641844B1 (en) | Modified carrier particles for use in dry powder inhalers | |
| Zeng et al. | The influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols | |
| JP6082049B2 (en) | Dry powder formulation of particles containing two or more active ingredients for the treatment of obstructive or inflammatory airway diseases | |
| JP3011770B2 (en) | Formulations for inhalation applications | |
| EP1196146B1 (en) | Powder particles with smooth surface for use in inhalation therapy | |
| EP1276473B1 (en) | Pharmaceutical formulations for dry powder inhalers | |
| US20110263492A1 (en) | Method to generate water soluble or nonwater soluble in nanoparticulates directly in suspension of dispersion media | |
| JPS6032714A (en) | Stabilized powdery pharmaceutical composition for application to nasal mucous membrane | |
| HU226982B1 (en) | Novel tiotropium-containing inhalation powder, process for its preperation and its use | |
| CN101378760A (en) | Pharmaceutical compositions comprising methotrexate | |
| CN103582484A (en) | Pulmonary delivery of 17-hydroxyprogesterone caproate (17-HPC) | |
| SK75198A3 (en) | Pharmaceutical composition | |
| WO2010094731A2 (en) | Pharmaceutical composition for inhalation | |
| JP2001151673A (en) | Production of powdery preparation for inhalation | |
| TWI296529B (en) | Solid peptide preparations for inhalation and their preparation | |
| Liu et al. | Role of dispersion enhancer selection in the development of novel tratinterol hydrochloride dry powder inhalation formulations | |
| KR20050008739A (en) | Powdery respiratory tonic composition | |
| KR20110096545A (en) | Dry powder pharmaceutical composition for inhalation | |
| JPWO2004087146A1 (en) | Method for producing fine particle mixture | |
| AU2004260699B2 (en) | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a PDE-4 inhibitor for treatment of asthma or chronic obstructive pulmonary disease | |
| WO2022127092A1 (en) | Trantinterol dry powder inhaler, preparation method therefor, and application thereof | |
| JP5698423B2 (en) | Process for the production of particles for use in pharmaceutical compositions | |
| CN108066329B (en) | Preparation method of microparticles of fluticasone or derivatives thereof for inhalation | |
| JP2001072586A (en) | Powdery inhaling preparation and its production | |
| JP2007512224A (en) | Treatment of asthma or chronic obstructive pulmonary disease combining dehydroepiandrosterone or dehydroepiandrosterone sulfate with a beta-agonist-containing bronchodilator |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Withdrawal of application because of no request for examination |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 20070605 |