JPH10218763A - Transpulmonary inhalation preparation and its production - Google Patents
Transpulmonary inhalation preparation and its productionInfo
- Publication number
- JPH10218763A JPH10218763A JP3846197A JP3846197A JPH10218763A JP H10218763 A JPH10218763 A JP H10218763A JP 3846197 A JP3846197 A JP 3846197A JP 3846197 A JP3846197 A JP 3846197A JP H10218763 A JPH10218763 A JP H10218763A
- Authority
- JP
- Japan
- Prior art keywords
- particles
- binder
- inhalation
- preparation
- granulated
- 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
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【0001】[0001]
【発明の属する技術分野】本発明は、経肺吸入用製剤及
びその製造方法に関し、より詳細には粒径分布がシャー
プでハンドリング性に優れ、1次粒子への崩壊、分散性
の良好な微細な造粒粒子よりなる経肺吸入用製剤および
その製造方法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preparation for pulmonary inhalation and a method for producing the same, and more particularly, to a fine particle having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles. The present invention relates to a preparation for pulmonary inhalation comprising fine granulated particles and a method for producing the same.
【0002】[0002]
【従来の技術】近年、ドラッグデリバリーシステム(D
DS)という概念の下に機器装置等との進歩とあいまっ
て幅広く製剤研究が行われるようになり、経口以外の新
投与経路製剤の発展の可能性が期待されている。なかで
も特に経肺吸入という投与方法は、肺の吸収部位の表面
積が極めて広いところから有利な投与経路であることが
知られている。2. Description of the Related Art In recent years, drug delivery systems (D
Under the concept of DS), a wide range of formulation studies has been conducted in conjunction with advances in equipment and the like, and the possibility of the development of new administration routes other than oral is expected. In particular, the administration method of transpulmonary inhalation is known to be an advantageous administration route because the surface area of the lung absorption site is extremely large.
【0003】例えば抗アレルギー剤等の薬液もしくは粉
末のエアゾールスプレー発生装置(例えば、ネブライザ
ーやスピンヘラー等)による噴霧液や飛散粉末(薬剤そ
のものの粉体粒子)の吸入用製剤等が有効な投与剤形で
あることが公知である。なかでもその使用性においては
粉末製剤のほうが簡便である。特に気管支喘息等の吸入
療法において、フロンガスを用いずに患者自身の吸入に
より薬物を吸入するドライパウダー吸入製剤の開発が注
目されている。ドライパウダー吸入製剤に要求される条
件としては、患者が薬物を吸入する際、肺への到達率が
高いとされる1〜7μmの空気力学径で薬物が吸入過程
で飛散することが必要とされ、近年粒径が1〜10μm
の粉体(ドライパウダー)に関わる粒子設計の研究が進
んできている。[0003] For example, an inhalation preparation of a spray solution or a scattered powder (powder particles of the drug itself) by an aerosol spray generator (eg, a nebulizer or a spin heller) of a drug solution or powder such as an antiallergic agent is effective. Is known. Among them, the powder preparation is more convenient in terms of its usability. In particular, in inhalation therapy for bronchial asthma and the like, development of a dry powder inhalation formulation for inhaling a drug by a patient's own inhalation without using Freon gas has attracted attention. The condition required for a dry powder inhalation formulation is that when a patient inhales a drug, the drug must be scattered in the inhalation process with an aerodynamic diameter of 1 to 7 μm, which is considered to have a high rate of reaching the lungs. In recent years, the particle size is 1 to 10 μm
Research on particle design related to powder (dry powder) has been progressing.
【0004】しかし、粒径の小さい微細な粒子の場合、
飛散しやすいだけでなく付着・凝集が生じやすく、また
流動性に劣る等の原因で、投与時に薬物がデバイスある
いはカプセル内部に付着し残留する等の製剤化や使用性
のうえでの難点がある。現在では粒子表面に流動性の良
好なさらに微細な粒子を付着させ表面処理することで改
善したり、担体等に吸着させたりする等の工夫が行われ
ているが充分ではなく、経肺吸入用粉体に関する粒子設
計の要望は高い。However, in the case of fine particles having a small particle size,
Not only is it easy to scatter, it is also easy to adhere and aggregate, and due to poor fluidity, etc., there are difficulties in formulation and usability such as the drug adheres and remains inside the device or capsule during administration. . At present, measures have been taken to improve the surface treatment by attaching finer particles with good fluidity to the particle surface, or to adsorb it to a carrier, etc. There is a high demand for particle design for powders.
【0005】既に本発明者らは、粒径が0.2mm以下
の微細な造粒物を調製するために転動攪拌流動層造粒法
およびワースター噴流層造粒法において高粘性、低粘性
の結合剤をスプレー液組成として用いて検討を行い、低
粘性の結合力の弱い結合剤を用いることで、出来るだけ
粒子表面をコーティングしつつ造粒を行う操作がコント
ロールしやすいことを見出し、微細な造粒物の製造方法
として出願を行っている(WO94/08709号公
報)。In order to prepare fine granules having a particle size of 0.2 mm or less, the present inventors have already conducted high-viscosity, low-viscosity A study was conducted using a binder as the spray liquid composition, and it was found that the operation of granulating while coating the particle surface as easily as possible was possible by using a low-viscosity binder with a weak binding force. An application has been filed as a method for producing a granulated product (WO94 / 08709).
【0006】また、高粘性(高結合力)の結合剤を使用
する場合、必要なスプレー液の使用量も少なく造粒の所
要時間も短いメリットがあるが、一部急激な造粒が進行
し粒子径の大きい粒子や団塊が産生するため、その粒径
分布のシャープさや目的とする粒径の粒子の収率につい
て改善の余地がある。一方、低粘性(低結合力)の結合
剤については必要なスプレー液の使用量も多く、造粒の
所要時間も長くその間に造粒物が物理的衝撃により粉化
しやすい欠点はあるが、造粒をできるだけ抑制する意味
で操作性は良い。さらに結合剤の展延性、浸透性が良好
であるならば粒子表面を効果的にコーティングしながら
造粒が進行し、望ましい微細粒子としての特性を有して
いることを見出している(平成6年度第11回製剤と粒
子設計シンポジウム講演要旨集、p165〜170、平
成7年度日本薬剤学会第11年会講演要旨集、p94〜
95)。When a binder having high viscosity (high binding force) is used, there is an advantage that the required amount of spray liquid is small and the time required for granulation is short. Since particles or aggregates having a large particle diameter are produced, there is room for improvement in the sharpness of the particle diameter distribution and the yield of particles having a target particle diameter. On the other hand, a low-viscosity (low-binding-force) binder requires a large amount of spray liquid to be used, and the required time for granulation is long. Operability is good in the sense of minimizing grains. Furthermore, if the spreadability and permeability of the binder are good, it is found that granulation proceeds while effectively coating the particle surface, and that it has desirable fine particle characteristics (1994). Proceedings of the 11th Symposium on Formulation and Particle Design, p165-170, Proceedings of the 11th Annual Meeting of the Japanese Pharmaceutical Society of Japan, p94-
95).
【0007】しかしながら、これらの報告で得られてい
る造粒粒子は経肺吸入用製剤において要求される吸入過
程での造粒粒子の崩壊、分散性を満足するものではな
い。[0007] However, the granulated particles obtained in these reports do not satisfy the disintegration and dispersibility of the granulated particles in the inhalation process required in the preparation for pulmonary inhalation.
【0008】[0008]
【発明が解決しようとする課題】従って、本発明の目的
は、粒径分布がシャープでハンドリング性に優れ、かつ
1次粒子への崩壊、分散性の良好な微細な造粒粒子より
なる経肺吸入用製剤を提供することにある。本発明の他
の目的は、本発明の経肺吸入用製剤の製造方法を提供す
ることにある。SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a pulmonary lung comprising fine granulated particles having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles. An inhalation formulation is provided. Another object of the present invention is to provide a method for producing the pulmonary inhalation preparation of the present invention.
【0009】[0009]
【課題を解決するための手段】本発明者らは、微細な1
次粒子を2次粒子に造粒することでハンドリング上の問
題点を克服しつつ、吸入過程で造粒粒子から1次粒子へ
の崩壊、分散が可能であれば造粒粒子が経肺吸入用の粉
体として有用であると考えた。この場合、2次粒子とし
ては出来るだけ微細かつ粒径分布のシャープな造粒粒子
であることが吸入性、ハンドリング性の観点で望ましい
が、従来このような特性を備えた精度の高い経肺吸入用
の造粒物は得られていない。本発明者らはこのような観
点から経肺吸入用の造粒粒子の設計に関して、鋭意検討
を行ったところ、意外にも低粘性、低結合性、良展延
性、浸透性を有する結合剤を用いて得られる結合剤の含
量が5重量%以下である平均粒子径が50μm以下の微
細な造粒粒子が1次粒子への崩壊、分散性に優れている
ことを見出し、本発明に到った。Means for Solving the Problems The present inventors have developed a fine 1
The granulated particles are used for transpulmonary inhalation if it is possible to break down and disperse the granulated particles into primary particles in the inhalation process while overcoming the handling problems by granulating the secondary particles into secondary particles. It was considered to be useful as a powder. In this case, it is desirable from the viewpoints of inhalability and handleability that the secondary particles are as fine as possible and granulated particles having a sharp particle size distribution, but conventionally, highly accurate transpulmonary inhalation having such characteristics is desirable. No granulated product has been obtained. The present inventors have conducted intensive studies on the design of granulated particles for pulmonary inhalation from such a viewpoint, and unexpectedly found a binder having low viscosity, low binding property, good spreadability, and permeability. The inventors have found that fine granulated particles having an average particle diameter of 50 μm or less, which has a binder content of 5% by weight or less, are excellent in disintegration into primary particles and dispersibility, and the present invention. Was.
【0010】即ち、本発明の要旨は、(1) 主薬を含
む粒子を粒子径が10μm以下の1次粒子とし、これに
結合剤を用いてコーティングしつつ造粒して得られる、
吸入過程で1次粒子への崩壊、分散性を示す平均粒子径
が50μm以下の微細な造粒粒子を含むことを特徴とす
る経肺吸入用製剤、(2) 造粒工程で転動、遠心、攪
拌、噴流およびパルスジェットエアー等の分散機構のい
ずれかを含む多機能型装置を用いて得られたものである
ことを特徴とする前記(1)記載の経肺吸入用製剤、
(3) 結合剤が粘度として2重量%水溶液で20℃下
で3.0センチポイズ以下のものであり、得られる造粒
粒子中に占める結合剤含量が5重量%以下であることを
特徴とする前記(1)又は(2)記載の経肺吸入用製
剤、(4) 結合剤がヒドロキシプロピルセルロースま
たはポリビニルピロリドンである前記(1)〜(3)い
ずれか記載の経肺吸入用製剤、(5) 前記(1)〜
(4)いずれかにおいて記載の造粒粒子が経肺吸入用デ
バイスに装填されてなる経肺吸入用製剤、(6) 転
動、遠心、攪拌、および噴流(ワースター形式を含む)
の1種以上を伴う複合型流動層装置を用い、主薬を含む
粒子径が10μm以下の1次粒子に、結合剤を含むスプ
レー液を噴霧して該1次粒子をコーティングしつつ造粒
を行い、吸入過程で1次粒子への崩壊、分散性を示す平
均粒子径が50μm以下の微細な造粒粒子とすることを
特徴とする、該造粒粒子を含む経肺吸入用製剤の製造方
法、(7) 造粒工程で転動、遠心、攪拌、噴流および
パルスジェットエアー等の分散機構のいずれかを含む多
機能型装置を用いることを特徴とする前記(6)記載の
製造方法、(8) 結合剤が粘度として2重量%水溶液
で20℃下で3.0センチポイズ以下のものであり、得
られる造粒粒子中に占める結合剤含量が5重量%以下で
あることを特徴とする前記(6)又は(7)記載の製造
方法、(9) 結合剤がヒドロキシプロピルセルロース
またはポリビニルピロリドンである前記(6)〜(8)
いずれか記載の製造方法、(10) 造粒粒子を経肺吸
入用デバイスに装填する工程をさらに含むことを特徴と
する前記(6)〜(9)いずれか記載の製造方法、に関
する。That is, the gist of the present invention is to (1) obtain particles obtained by forming particles containing a main drug into primary particles having a particle diameter of 10 μm or less and coating them with a binder while granulating them.
Transpulmonary inhalation preparation characterized by containing fine granulated particles having an average particle diameter of 50 μm or less, which show disintegration into primary particles and dispersibility in the inhalation process, (2) rolling and centrifugation in the granulation step The preparation for transpulmonary inhalation according to the above (1), which is obtained by using a multifunctional device including any of a dispersion mechanism such as stirring, jetting, and pulse jet air.
(3) The binder is a 2% by weight aqueous solution having a viscosity of not more than 3.0 centipoise at 20 ° C. and the binder content in the obtained granulated particles is not more than 5% by weight. The preparation for pulmonary inhalation according to the above (1) or (2), (4) the preparation for pulmonary inhalation according to any of the above (1) to (3), wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone, (5) ) (1)-
(4) a preparation for transpulmonary inhalation, wherein the granulated particles according to any of the above are loaded in a transpulmonary inhalation device, (6) tumbling, centrifugation, stirring, and jetting (including a Wurster type)
Using a composite fluidized bed apparatus with at least one of the following, a spray liquid containing a binder is sprayed onto primary particles having a particle diameter of 10 μm or less containing the main agent to perform granulation while coating the primary particles. A method for producing a preparation for transpulmonary inhalation containing the granulated particles, characterized in that the granulated particles exhibit an average particle size of 50 μm or less which exhibits disintegration and disintegration into primary particles during the inhalation process. (7) The production method according to (6), wherein a multifunctional device including any of a dispersion mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air is used in the granulation step. The above-mentioned (2), wherein the binder is a 2% by weight aqueous solution having a viscosity of not more than 3.0 centipoise at 20 ° C. and the binder content in the obtained granulated particles is not more than 5% by weight. 6) or the production method according to (7), wherein (9) the binder is (6) to (8), which are hydroxypropylcellulose or polyvinylpyrrolidone
(10) The method according to any one of (6) to (9), further including a step of loading the granulated particles into a transpulmonary inhalation device.
【0011】[0011]
【発明の実施の形態】本発明の経肺吸入用製剤は、主薬
を含む粒子を粒子径が10μm以下の1次粒子とし、こ
れに結合剤を用いてコーティングしつつ造粒して得られ
る、吸入過程で1次粒子への良好な崩壊、分散性を示す
平均粒子径が50μm以下の微細な造粒粒子を含むこと
を特徴とする。本発明の経肺吸入用製剤に用いる造粒粒
子は、転動、遠心、攪拌、および噴流(ワースター形式
を含む)の1種以上を伴う複合型流動層装置を用い、主
薬を含む粒子径が10μm以下の1次粒子に、結合剤を
含むスプレー液を噴霧して該1次粒子をコーティングし
つつ造粒を行うことによって製造されるものであり、平
均粒子径が50μm以下であって粒子径は実質的に10
0μm以下のものである。BEST MODE FOR CARRYING OUT THE INVENTION The pulmonary inhalation preparation of the present invention is obtained by forming particles containing a main drug into primary particles having a particle size of 10 μm or less, and granulating the particles while coating them with a binder. It is characterized by containing fine granulated particles having an average particle diameter of 50 μm or less, which show good disintegration into primary particles and dispersibility in the inhalation process. The granulated particles used in the preparation for transpulmonary inhalation of the present invention use a composite fluidized bed apparatus involving at least one of tumbling, centrifugation, stirring, and jetting (including a Wurster type), and the particle diameter including the principal drug is used. It is manufactured by spraying a spray liquid containing a binder onto primary particles of 10 μm or less and performing granulation while coating the primary particles. The average particle size is 50 μm or less and the particle size is Is substantially 10
It is less than 0 μm.
【0012】ここで、造粒粒子の粒子径が実質的に10
0μm以下であるとは、100μm以下の粒子径のもの
を少なくとも97重量%以上占めていることを意味す
る。平均粒子径が50μmより大きく、100μmを超
える粒子が多く存在することは造粒粒子中の結合剤含量
が高く、結合の強い粒子が成長していることであり、有
用率(使用率)がそれだけ低くなるので好ましくない。
また、本明細書において粒子径は篩により測定されたも
のをいい、平均粒子径は50%の重量百分率を示す粒径
をいう。Here, the particle size of the granulated particles is substantially 10
0 μm or less means that particles having a particle diameter of 100 μm or less account for at least 97% by weight or more. The presence of a large number of particles having an average particle diameter of more than 50 μm and exceeding 100 μm means that the binder content in the granulated particles is high and that particles having a strong bond are growing, and the useful rate (use rate) is only that much. It is not preferable because it becomes low.
Further, in the present specification, the particle size refers to a value measured by a sieve, and the average particle size refers to a particle size showing a weight percentage of 50%.
【0013】本発明の経肺吸入用製剤に用いる造粒粒子
の平均粒子径は、1次粒子への良好な崩壊、分散性の上
で結合剤含量のバランスの点から50μm以下であるの
が好ましく、40μm以下であるのがさらに好ましい。The average particle size of the granulated particles used in the preparation for pulmonary inhalation of the present invention should be 50 μm or less from the viewpoint of good disintegration into primary particles and good balance of the binder content in view of dispersibility. More preferably, it is 40 μm or less.
【0014】本発明の経肺吸入用製剤は、前記のように
転動、遠心、攪拌、および噴流(ワースター形式を含
む)の1種以上を伴う複合型流動層装置を用い、主薬を
含む粒子径が10μm以下の粒子(以下、原料粒子と呼
ぶ場合がある)の流動層を形成しつつ、低粘性、低結合
性、良展延性、浸透性を有する結合剤を含むスプレー液
を噴霧しながらコーティングしつつ造粒を進行させて得
られる結合剤の含量が5重量%以下で平均粒子径が50
μm以下の微細な造粒粒子を含むものである。該造粒粒
子の製造においては、噴霧されるスプレー液の液滴のう
ち粒径30μm以上の粗液滴が10体積%以下になるよ
うに制御され、さらには排気温度が装置設置環境下の断
熱飽和温度より高くなるよう、好ましくは3℃以上高く
なるようにスプレー液の噴霧量が制御されているのが好
ましい。[0014] The preparation for transpulmonary inhalation of the present invention uses a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type) as described above, and comprises a particle containing a main drug. While forming a fluidized bed of particles having a diameter of 10 μm or less (hereinafter sometimes referred to as raw material particles), while spraying a spray liquid containing a binder having low viscosity, low binding property, good spreadability, and permeability. The binder content obtained by advancing granulation while coating is 5% by weight or less and the average particle size is 50%.
It contains fine granulated particles of μm or less. In the production of the granulated particles, coarse droplets having a particle diameter of 30 μm or more are controlled so as to be 10% by volume or less among the droplets of the spray liquid to be sprayed, and the exhaust temperature is further reduced by the heat insulation under the installation environment of the apparatus. The spray amount of the spray liquid is preferably controlled so as to be higher than the saturation temperature, preferably higher than 3 ° C.
【0015】本発明において用いられる複合型流動層装
置としては、転動、遠心、攪拌、および噴流(ワースタ
ー形式を含む)の1種以上を伴う複合型流動層装置であ
れば特に限定されることはなく、公知の装置が使用でき
る。The composite fluidized bed apparatus used in the present invention is not particularly limited as long as it is a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type). However, a known device can be used.
【0016】具体的には、例えば、ワースター(グラッ
ト社製)、スパイラフロー(フロイント産業(株)
製)、マルチプレックス(パウレック(株)製)、スピ
ラコータ(岡田精工(株)製)、アグロマスター(細川
ミクロン(株)製)、ニューマルメライザー(不二パウ
ダル(株)製)等が用いられる。More specifically, for example, Worster (manufactured by Glatt), Spiral Flow (Freund Sangyo Co., Ltd.)
), A multiplex (manufactured by Powrex Co., Ltd.), a spira coater (manufactured by Okada Seiko Co., Ltd.), an agromaster (manufactured by Hosokawa Micron Co., Ltd.), and a new marmalizer (manufactured by Fuji Paudal Co., Ltd.). .
【0017】本発明における具体的な造粒操作は、例え
ば、あらかじめ粉砕等で調製した粒子径が10μm以下
の主薬を含む粒子、即ち、主薬または主薬および各種の
所望の添加剤を含む粒子(1次粒子)である原料粒子を
上記の複合型流動層造粒装置に仕込み、さらに装置内で
の流動性確保の目的で要すれば、最初に少量の水をスプ
レー噴霧したり、少量の流動性改善剤、例えばアエロジ
ル(日本アエロジル工業(株)製)等を適宜加えた後、
該原料粒子の流動層を形成しつつ、結合剤を適当な濃度
で含むスプレー液を必要量噴霧すればよい。In the specific granulation operation in the present invention, for example, particles containing a main agent having a particle diameter of 10 μm or less, which has been prepared in advance by pulverization or the like, that is, particles containing the main agent or the main agent and various desired additives (1) The raw material particles as the secondary particles) are charged into the above-mentioned composite fluidized bed granulator, and if necessary for the purpose of ensuring fluidity in the device, a small amount of water is first sprayed or sprayed. After appropriately adding an improving agent such as Aerosil (manufactured by Nippon Aerosil Industry Co., Ltd.),
A required amount of a spray liquid containing a binder at an appropriate concentration may be sprayed while forming a fluidized bed of the raw material particles.
【0018】本発明で用いる結合剤は、低粘性、低結合
性、良展延性、及び浸透性等の特性を備えた結合剤を用
いるのが好ましく、例えばヒドロキシプロピルセルロー
スのSSLグレード(HPC−SSL(日本曹達(株)
製))、ポリビニルピロリドン(PVP)の Kollidon
12PF、 Kollidon 17PF 、 Kollidon 25、 Kollidon DA64の
グレード(BASF(株)製)、ヒドロキシプロピルメ
チルセルロース等のように20℃での2重量%水溶液の
粘度が3.0センチポイズ以下の結合剤が使用される。As the binder used in the present invention, it is preferable to use a binder having characteristics such as low viscosity, low binding, good spreadability, and permeability. For example, SSL grade of hydroxypropylcellulose (HPC-SSL) (Nippon Soda Co., Ltd.
Kollidon of polyvinylpyrrolidone (PVP)
A binder such as 12PF, Kollidon 17PF, Kollidon 25, Kollidon DA64 grade (manufactured by BASF), hydroxypropyl methylcellulose, etc., having a 2% by weight aqueous solution at 20 ° C and having a viscosity of 3.0 centipoise or less is used. .
【0019】本発明において、種々の造粒粒子を調製し
てその1次粒子への崩壊、分散性の容易さを評価して経
肺吸入用の粉末としての適正をみると、平均粒子径が5
0μm以下で小さいほど、かつ結合剤の造粒粒子中の含
量が5重量%以下で少ないほど、1次粒子への崩壊、分
散性の程度が大きくなる傾向が観察された。即ち、低結
合性結合剤のヒドロキシプロピルセルロースやポリビニ
ルピロリドンの必要量は造粒粒子中に占める結合剤含量
が5重量%以下であり、さらに好ましくは4重量%以下
であり、少なければ少ないほど粒子強度及び粒子径は小
さい方向にシフトするが、あまり結合剤含量が小さいと
壊れやすくハンドリング性に難がでるので、少なくとも
2重量%以上は必要である。結合剤含量が5重量%を越
えると平均粒子径が大きくなり粒子強度が強くなる傾向
がみられ、所望の崩壊、分散効果が期待できなくなる。
また、造粒時に界面活性剤やステアリン酸マグネシウム
等の添加剤を得られる造粒粒子の崩壊促進、流動化改善
等の目的で添加し造粒することも可能であるし、これら
の添加剤を造粒後に添加することもできる。In the present invention, various granulated particles are prepared, and their disintegration into primary particles and easiness of dispersibility are evaluated to determine the suitability as a powder for transpulmonary inhalation. 5
It was observed that the smaller the particle size was 0 μm or less and the smaller the content of the binder in the granulated particles was 5% by weight or less, the larger the degree of disintegration into primary particles and the degree of dispersibility increased. That is, the required amount of the low-binding binder hydroxypropylcellulose or polyvinylpyrrolidone is such that the binder content in the granulated particles is 5% by weight or less, more preferably 4% by weight or less. Although the strength and the particle size shift in the direction of being small, if the content of the binder is too small, it is fragile and the handling property becomes difficult. Therefore, at least 2% by weight or more is necessary. If the binder content exceeds 5% by weight, the average particle diameter tends to increase and the particle strength tends to increase, so that the desired disintegration and dispersion effects cannot be expected.
It is also possible to add additives such as surfactants and magnesium stearate during granulation to promote the disintegration of granulated particles, to add and granulate for the purpose of improving fluidization, and to use these additives. It can also be added after granulation.
【0020】本発明において結合剤を噴霧する際のスプ
レーの方式は、装置の底部から少し上の位置から下部に
向けてのトップスプレーでも、底部から上部に向けての
ボトムスプレーでも、また底部において接線方向に向け
てのタンジェンシャル(サイド)スプレーでもかまわな
いが、例えば粒子径が数十μmのより小さな造粒粒子で
粒径分布のシャープな造粒粒子を得ようとする場合、ボ
トム又はタンジェンシャル(サイド)のスプレー様式を
選択すればよい。また、種々の様式を組み合わせて噴霧
することもできる。In the present invention, the method of spraying the binder may be a top spray from a position slightly above the bottom of the apparatus to the bottom, a bottom spray from the bottom to the top, or a bottom spray from the bottom. A tangential (side) spray in the tangential direction may be used. For example, when it is desired to obtain granulated particles having a sharp particle size distribution with smaller granulated particles having a particle size of several tens of μm, a bottom or tangential spray is required. It is only necessary to select the spray style of the tangential (side). It is also possible to spray by combining various modes.
【0021】また、スプレー液の液滴径が微小なほど、
且つその液滴径分布がシャープなほど、コーティングし
つつ徐々に造粒してシャープな粒径分布を有する造粒粒
子を調製するうえで有利である。従って、本発明におい
ては適当なスプレー液組成と濃度、スプレー風量を適宜
選択すればよい。スプレーノズルの性能がスプレー液の
液滴径に影響を与えるが、通常の装置に用いられている
ものを適宜選択すればよい。Further, the smaller the droplet diameter of the spray liquid is,
Further, the sharper the droplet diameter distribution, the more advantageous it is in preparing granulated particles having a sharp particle diameter distribution by gradually granulating while coating. Therefore, in the present invention, an appropriate spray liquid composition, concentration, and spray air volume may be appropriately selected. The performance of the spray nozzle affects the droplet diameter of the spray liquid, but the one used in a usual apparatus may be appropriately selected.
【0022】なお、原料粒子やコーティングされたもの
や造粒進行中の粒子を含め、これらの粒子の流動層を形
成するためには、通常、加温された空気等が用いられ
る。In order to form a fluidized bed of these particles, including raw material particles, coated particles, and particles undergoing granulation, heated air or the like is usually used.
【0023】本発明における結合剤は、低粘性、低結合
力、良展延性、及び浸透性等の特性を有することが重要
であり、このような機能を有するものとして、前述のヒ
ドロキシプロピルセルロース、ポリビニルピロリドン、
ヒドロキシプロピルメチルセルロース等を適当な希釈剤
(例えば、乳糖、ブドウ糖等の糖類、アミノ酸等の輸液
類)や添加剤の添加により適宜調製して使用することが
できる。この場合、結合剤をエタノール等の溶媒に溶解
して用いることも可能であるが、操作性等から水系で使
用することが望ましい。またスプレー液の液滴径、粘
度、結合力、良展延性等の上記目的の機能性を損なわな
い範囲で界面活性剤等の添加剤をスプレー液に添加する
こともできる。また目的や操作性等の理由から低結合性
結合剤水溶液と種々の目的の添加剤(基剤)を含む低結
合性結合剤を適宜使い分けすることも可能である。ま
た、連続的もしくは段階的にスプレー液の成分や組成を
変えることもできる。勿論、これらの添加については出
来るだけ少量であることが望ましい。It is important that the binder in the present invention has characteristics such as low viscosity, low bonding strength, good spreadability, and permeability. Polyvinylpyrrolidone,
Hydroxypropyl methylcellulose and the like can be appropriately prepared by adding a suitable diluent (for example, sugars such as lactose and glucose, and infusions such as amino acids) and additives, and used. In this case, it is possible to use the binder by dissolving it in a solvent such as ethanol, but it is preferable to use the binder in an aqueous system from the viewpoint of operability and the like. Further, an additive such as a surfactant may be added to the spray liquid within a range not impairing the above-mentioned functional properties such as the droplet diameter, viscosity, bonding strength, and good spreadability of the spray liquid. It is also possible to appropriately use a low-binding binder aqueous solution and a low-binding binder containing additives (bases) for various purposes for reasons such as purpose and operability. Further, the components and compositions of the spray liquid can be changed continuously or stepwise. Of course, it is desirable that these additions be as small as possible.
【0024】スプレー液の粘度は、上記目的の機能性や
操作性の観点から20℃での粘度が20センチポイズ以
下であることが望ましく、15センチポイズ以下である
ことがより望ましい。スプレー液中の結合剤の濃度は、
コーティング効率と造粒の所要時間等との兼ね合いで5
〜20重量%程度の結合剤水溶液が好ましく用いられ
る。例えば、結合剤がHPC−SSLの場合、5〜8重
量%では20℃での粘度は6〜15センチポイズとな
る。PVPの場合、5〜20重量%では20℃での粘度
は1〜10センチポイズとなる。The viscosity of the spray liquid at 20 ° C. is desirably 20 centipoise or less, and more desirably 15 centipoise or less, from the viewpoint of the above-mentioned functions and operability. The concentration of the binder in the spray liquid is
5 in consideration of coating efficiency and required time for granulation
A binder aqueous solution of about 20% by weight is preferably used. For example, when the binder is HPC-SSL, the viscosity at 20 ° C. becomes 6 to 15 centipoise at 5 to 8% by weight. In the case of PVP, the viscosity at 20 ° C. at 5 to 20% by weight is 1 to 10 centipoise.
【0025】本発明におけるスプレー液滴の液滴径分布
は、噴霧されるスプレー液の液滴のうち、粒径30μm
以上の粗液滴が10体積%以下になるように制御されて
いることが好ましく、30μm以上の粗液滴が8体積%
以下に制御されていることがより好ましい。このように
スプレー液滴中の粗液滴の割合を低くしてできるだけシ
ャープな粒径分布を有する微小液滴とすることにより、
コーティングを行いながら造粒を進行させ、得られる造
粒粒子の粒径分布をシャープにすることができる。この
ようにスプレー液の液滴径を制御するには、上記のよう
に結合剤の種類や濃度等によりスプレー液の粘度を調製
したり、スプレー液の送液速度やスプレー空気風量を調
整したりすること等により行うことができる。In the present invention, the droplet diameter distribution of the spray droplets is as follows.
It is preferable that the above coarse droplets are controlled to be 10% by volume or less, and the coarse droplets of 30 μm or more are controlled to 8% by volume.
More preferably, it is controlled as follows. By reducing the proportion of the coarse droplets in the spray droplets to make the droplets as sharp as possible in this manner,
Granulation can be advanced while performing coating, and the particle size distribution of the obtained granulated particles can be sharpened. In order to control the droplet diameter of the spray liquid in this manner, as described above, the viscosity of the spray liquid is adjusted according to the type and concentration of the binder, or the flow rate of the spray liquid and the air volume of the spray air are adjusted. Can be performed.
【0026】スプレー液として、例えばHPC−SSL
水溶液を使用する場合、粗液滴の割合はそれほど高くは
なく、仮に数体積%程度の粗液滴が存在しても結合力は
そんなに強くないので造粒の支配因子とはならない。例
えば、HPC−SSLの5重量%水溶液においては、ス
プレー空気風量が30〜35L/分の条件下で、スプレ
ー液の送液速度の調整により液滴径の平均粒子径
(d50)は約10μm前後で粒径30μm以上の粗液滴
を5〜6体積%以下とすることができる。ここでいうス
プレー液の液滴径は、レーザー光散乱式粒度分布測定装
置(例えば、東日コンピューターアピリケーションズ
(株)製、LSDA−2400A)により測定すること
ができる。As a spray liquid, for example, HPC-SSL
When an aqueous solution is used, the ratio of coarse droplets is not so high, and even if coarse droplets of about several volume% are present, the binding force is not so strong, so that it does not become a controlling factor for granulation. For example, in a 5% by weight aqueous solution of HPC-SSL, the average particle diameter (d 50 ) of the droplet diameter is about 10 μm by adjusting the liquid sending speed of the spray liquid under the condition that the spray air flow rate is 30 to 35 L / min. The coarse droplets having a particle size of 30 μm or more before and after can be reduced to 5 to 6% by volume or less. The droplet diameter of the spray liquid mentioned here can be measured by a laser light scattering type particle size distribution measuring device (for example, LSDA-2400A, manufactured by Tonichi Computer Applications).
【0027】スプレー液の送液速度は、流動層内の温度
コントロールと密接な関係を有し造粒に影響を与える因
子である。即ち、造粒操作時の環境(温度、湿度)で決
まる断熱飽和温度への断熱冷却曲線にそった装置入口の
送風加熱空気温度から製品温度、排気温度への冷却につ
いて検討、考察を試みると、排気温度が断熱飽和温度よ
り高くなるにつれ、そのときのスプレー液は粒子へのコ
ーティング性の付加の程度を高めながら送液され造粒が
進行することが理解された。さらに充分なコーティング
が進行しつつ造粒されるためには排気温度が断熱飽和温
度より少なくとも3℃以上となるようスプレー液が供給
される必要がある。好ましくは排気温度が断熱飽和温度
より3〜7℃高いことがより好ましい。排気温度が断熱
飽和温度より7℃を越えて高くなりすぎるとスプレー液
の送液が遅くなり効率的ではないし、スプレー液の液滴
の乾燥度が高まり粒子への噴霧、付着が均一におこらな
くなり不都合をもたらす。排気温度が断熱飽和温度より
低いと、スプレー液の供給が過剰となり流動層内の粒子
が濡れすぎて流動性が低下し、団塊等が生成しトラブル
の原因となる。The feed rate of the spray liquid is closely related to the temperature control in the fluidized bed and is a factor that affects granulation. In other words, when examining and considering cooling from the blast heating air temperature at the device inlet to the product temperature and exhaust temperature along the adiabatic cooling curve to the adiabatic saturation temperature determined by the environment (temperature, humidity) during the granulation operation, It was understood that as the exhaust temperature became higher than the adiabatic saturation temperature, the spray liquid at that time was sent while increasing the degree of addition of the coating property to the particles, and the granulation proceeded. In order for the granulation to proceed while sufficient coating proceeds, it is necessary to supply the spray liquid so that the exhaust temperature is at least 3 ° C. higher than the adiabatic saturation temperature. More preferably, the exhaust temperature is 3 to 7 ° C. higher than the adiabatic saturation temperature. If the exhaust gas temperature is higher than the adiabatic saturation temperature by more than 7 ° C., the delivery of the spray liquid will be slow and inefficient, and the spray liquid droplets will dry more and the spraying and adhesion to the particles will not be uniform. Brings inconvenience. If the exhaust temperature is lower than the adiabatic saturation temperature, the supply of the spray liquid becomes excessive, and the particles in the fluidized bed become too wet and the fluidity is reduced, and agglomerates and the like are generated to cause trouble.
【0028】即ち、造粒粒子としての粒径分布のシャー
プさは、上記の低粘性、低結合力、良展延性、及び浸透
性を有する適当な結合剤を用い、上記の操作条件のもと
に断熱飽和温度より高い温度でコーティングしつつ造粒
することにより、主薬をベースとした1次粒子を原料粒
子として粒径分布のシャープな粒子表面の平滑度の高
い、1次粒子への崩壊、分散性の良好な造粒粒子を提供
することができるが、この場合、断熱飽和温度より3〜
7℃高く制御されるのが好ましい。That is, the sharpness of the particle size distribution as the granulated particles is determined by using an appropriate binder having the above-mentioned low viscosity, low binding force, good spreadability, and permeability under the above operating conditions. By granulating while coating at a temperature higher than the adiabatic saturation temperature, primary particles based on the main drug are used as raw material particles, and the particle surfaces with sharp particle size distribution have high smoothness and collapse into primary particles, Granulated particles having good dispersibility can be provided.
Preferably, the temperature is controlled to be 7 ° C. higher.
【0029】このように底部のディスクローターの攪拌
により粉体の転動、攪拌による造粒と粉化のバランスが
あるとはいえ、断熱飽和温度を考慮した排気温度のコン
トロールは重要な因子である。もしこのような円滑な排
気温度制御がなされなければ団塊ができたりして不均一
な造粒が進行することになり操作を停止せざるをえなく
なる。As described above, although there is a balance between the rolling of the powder by the agitation of the bottom disk rotor and the granulation and the pulverization by the agitation, the control of the exhaust temperature in consideration of the adiabatic saturation temperature is an important factor. . If such smooth exhaust temperature control is not performed, agglomeration may occur and uneven granulation will proceed, and the operation must be stopped.
【0030】ローターの攪拌速度については、それを適
宜調整することにより造粒粒子の粒径分布を調整でき
る。一般に攪拌速度が高いとより微細な方向に粒径をシ
フトさせることが可能であるが、このときスプレー条件
を結合剤濃度とスプレー量の視点で考慮することにより
微粉の発生を阻止することができ粒径分布をシャープに
保つことができる。The particle size distribution of the granulated particles can be adjusted by appropriately adjusting the stirring speed of the rotor. Generally, when the stirring speed is high, the particle size can be shifted in a finer direction.However, at this time, the generation of fine powder can be prevented by considering the spray conditions from the viewpoint of the binder concentration and the spray amount. The particle size distribution can be kept sharp.
【0031】スプレー液の噴霧速度は自ずから上記因子
に支配されることになり、低粘性、低結合性で良好な展
延性、浸透性を有する結合剤のスプレー溶液を噴霧する
ことで粗大な粒子成長は抑制され、むしろ底部でのロー
ターによる攪拌、転動作用もしくは流動作用による粉化
とのバランスはあるが、微粉をコーティングしつつ造粒
する方向にむける結果となり粒径分布をシャープにする
上で良好な結果をもたらすことになる。The spraying rate of the spray liquid is naturally governed by the above factors, and coarse particles grow by spraying a spray solution of a binder having low viscosity, low binding property, good spreadability and permeability. Is suppressed, but rather there is a balance with stirring by the rotor at the bottom, pulverization due to rolling action or flow action, but it results in the direction of granulation while coating fine powder, and in sharpening the particle size distribution It will give good results.
【0032】原料粒子や造粒過程の粒子は底部でディス
クローターの回転による攪拌、転動が行われる装置の場
合には、底部で攪拌、転動および上部に向かっての流動
や下部への下降と動きながらスプレーと流動乾燥を繰り
返していくが、底部のディスクローターの回転速度を高
くしたり流動層内の空気量をあげることで粒子運動はよ
り活発になり、より微細な方へ粉化がおこる。またパル
スジェットエアーによる分散機構を作用させて空気の流
れを粒子に対して向流方向に与えることでこのような複
雑な現象を容易にコントロールすることができ、シャー
プな粒径分布を有する微細な造粒粒子を経肺吸入用粒子
(ドライパウダー)として設計、提供することもでき
る。即ち、本発明では造粒工程で転動、遠心、攪拌、噴
流およびパルスジェットエアー等の分散機構のいずれか
を含む多機能型装置を用いるのが好適である。In the case of a device in which the raw material particles and the particles in the granulation process are stirred and rolled by rotating the disk rotor at the bottom, stirring, rolling and flowing toward the upper portion and descending to the lower portion are performed at the bottom portion. Spraying and fluid drying are repeated while moving, but by increasing the rotation speed of the disk rotor at the bottom and increasing the amount of air in the fluidized bed, the particle movement becomes more active and powdering to finer particles Get offended. In addition, it is possible to easily control such complicated phenomena by giving the air flow in the countercurrent direction to the particles by operating the dispersion mechanism by pulse jet air, and it is possible to control fine particles with a sharp particle size distribution. The granulated particles can also be designed and provided as particles for pulmonary inhalation (dry powder). That is, in the present invention, it is preferable to use a multifunctional device including any of a dispersion mechanism such as rolling, centrifugation, stirring, jet flow, and pulse jet air in the granulation step.
【0033】本発明の経肺吸入用製剤は、以上の製造方
法により得られる造粒粒子をベースにして、また、造粒
粒子を経肺吸入用デバイスに常法により装填して経肺吸
入用製剤としてもよい。本発明における経肺吸入用デバ
イスとしては、特に限定されることはなく、例えば、ネ
ブライザーやスピンヘラー等が挙げられる。本発明のこ
のような製剤にあっては、吸入過程で微細な1次粒子に
速やかに崩壊、分散することから、主薬をベースとした
1次粒子の肺への到達性が良好となり、極めて良好な経
肺吸収性が達成される。本発明の経肺吸入用製剤におい
て対象となる主薬としては、経肺吸収性のある薬物であ
れば特に限定されない。例えば、クロモグリク酸ナトリ
ウム、硫酸サルブタモール、フマル酸ケトチフェンのよ
うな抗アレルギー剤(気管支喘息治療剤)にみられる呼
吸器系に作用する薬剤は勿論のこと、インシュリン、C
SF(顆粒状コロニー刺激因子)等のペプチド薬物にも
適用が可能である。後述の実施例では抗炎症剤のジクロ
フエナクナトリウムをモデルとして検討している。The preparation for pulmonary inhalation according to the present invention is based on the granulated particles obtained by the above-mentioned production method, and the granulated particles are loaded into a device for pulmonary inhalation by a conventional method. It may be a formulation. The device for transpulmonary inhalation in the present invention is not particularly limited, and includes, for example, a nebulizer and a spinner. In such a preparation of the present invention, the primary particles based on the main drug reach the lungs very well because they rapidly disintegrate and disperse into fine primary particles in the inhalation process, and are extremely good. A good transpulmonary absorption is achieved. The target drug in the pulmonary inhalation preparation of the present invention is not particularly limited as long as it is a pulmonary absorbable drug. For example, drugs that act on the respiratory system found in antiallergic agents (therapeutic agents for bronchial asthma) such as sodium cromoglycate, salbutamol sulfate, and ketotifen fumarate, as well as insulin, C
It is also applicable to peptide drugs such as SF (granular colony stimulating factor). In the examples described later, diclofenac sodium as an anti-inflammatory agent is examined as a model.
【0034】[0034]
【実施例】以下、実施例、比較例および試験例により本
発明をさらに詳しく説明するが、本発明はこれらの実施
例等によりなんら限定されるものではない。The present invention will be described in more detail with reference to the following Examples, Comparative Examples and Test Examples, but the present invention is not limited to these Examples.
【0035】実施例1 局方ジクロフエナクナトリウムを粉砕することにより得
たジクロフエナクナトリウム微粉砕粒子(平均粒子径5
μm以下)470gに対して2重量%相当の量にあたる
アエロジル#200(日本アエロジル工業(株)製)を
添加し、転動流動層造粒装置アグロマスター(ホソカワ
ミクロン(株)製)に投入し、60℃に加温した12〜
15m3 /hrの空気量を流動層内に送風しながら底部
で300rpmの回転速度でディスクローターを回転し
粉体を転動、かつ流動させた。スプレー液の組成はHP
C−SSL5重量%水溶液とし、4.5〜3.5g/m
inのスプレー速度でタンジェンシャル(サイド)スプ
レー様式にて470gの噴霧を行った時点で造粒を終了
し、本発明造粒品Iを得た。このときのスプレー空気量
は30〜26L/min、出口空気温度は27〜26.
5℃であり、断熱飽和温度より4℃高い条件とした。本
発明造粒品Iの平均粒子径(d50)は45μmであり、
結合剤の造粒品中含量は約4.6重量%であった。ま
た、100μm以下の造粒粒子が約97%であった。Example 1 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (manufactured by Nippon Aerosil Industry Co., Ltd.) equivalent to 2% by weight based on 470 g) was added to 470 g, and the mixture was introduced into a tumbling fluidized bed granulator Agromaster (manufactured by Hosokawa Micron Corp.). 12 ~ heated to 60 ° C
While blowing an air amount of 15 m 3 / hr into the fluidized bed, the disk rotor was rotated at a rotation speed of 300 rpm at the bottom to roll and flow the powder. The composition of the spray liquid is HP
C-SSL 5% by weight aqueous solution, 4.5 to 3.5 g / m
At the time when 470 g of the tangential (side) spray was sprayed at a spray rate of "in", the granulation was terminated, and a granulated product I of the present invention was obtained. The spray air amount at this time is 30 to 26 L / min, and the outlet air temperature is 27 to 26.L / min.
5 ° C., which was 4 ° C. higher than the adiabatic saturation temperature. The average particle size (d 50 ) of the granulated product I of the present invention is 45 μm,
The content of the binder in the granulated product was about 4.6% by weight. Further, about 97% of the granulated particles had a size of 100 μm or less.
【0036】実施例2 局方ジクロフエナクナトリウムを粉砕することにより得
たジクロフエナクナトリウム微粉砕粒子(平均粒子径5
μm以下)500gに対して0.62重量%相当の量に
あたるアエロジル#200(日本アエロジル工業(株)
製)を添加し、転動流動層造粒装置アグロマスター(ホ
ソカワミクロン(株)製)に投入し、60℃に加温した
12〜17m3 /hrの空気量を流動層内に送風しなが
ら底部300rpmの回転速度でディスクローターを回
転し粉体を転動、かつ流動させた。また造粒の過程でパ
ルスジェットエアーを対向流式で送り(2秒のインター
バル時間に対して0.3秒の間欠的噴射)、分散効果を
発揮させた。スプレー液の組成はHPC−SSL5重量
%水溶液とし、3.5〜6.5g/minのスプレー速
度でタンジェンシャル(サイド)スプレー様式にて50
0gの噴霧を行った時点で造粒を終了し、本発明造粒品
IIを得た。このときのスプレー空気量は27L/mi
n、出口空気温度は32〜28℃であり、断熱飽和温度
よりも4〜7℃高い条件とした。本発明造粒品IIの平均
粒子径(d50)は34μmであり、結合剤の造粒品中含
量は約4.7重量%であった。また、100μm以下の
造粒粒子が約99%であった。Example 2 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (Nippon Aerosil Industry Co., Ltd.), equivalent to 0.62% by weight based on 500 g
Manufactured by Hosokawa Micron Co., Ltd.), and an air volume of 12 to 17 m 3 / hr heated to 60 ° C. is blown into the fluidized bed, and the bottom portion is formed. The powder was rolled and flowed by rotating the disk rotor at a rotation speed of 300 rpm. In the granulation process, pulse jet air was sent in a counter-current system (intermittent ejection of 0.3 seconds for an interval time of 2 seconds) to exert a dispersion effect. The composition of the spray liquid is a 5% by weight aqueous solution of HPC-SSL, and is 50 in a tangential (side) spray mode at a spray rate of 3.5 to 6.5 g / min.
When the spraying of 0 g is performed, the granulation is finished, and the granulated product of the present invention is obtained.
I got II. The spray air volume at this time is 27 L / mi
n, the outlet air temperature was 32 to 28 ° C., which was 4 to 7 ° C. higher than the adiabatic saturation temperature. The average particle diameter (d 50 ) of the granulated product II of the present invention was 34 μm, and the content of the binder in the granulated product was about 4.7% by weight. Further, about 99% of granulated particles having a size of 100 μm or less were used.
【0037】実施例3 局方ジクロフエナクナトリウムを粉砕することにより得
たジクロフエナクナトリウム微粉砕粒子(平均粒子径5
μm以下)500gに対して2重量%相当の量にあたる
アエロジル#200(日本アエロジル工業(株)製)を
添加し、転動流動層造粒装置アグロマスター(ホソカワ
ミクロン(株)製)に投入し、60℃に加温した12〜
15m3 /hrの空気量を流動層内に送風しながら底部
で300rpmの回転速度でディスクローターを回転し
粉体を転動、かつ流動させた。スプレー液の組成はKoll
idon 25 の5重量%水溶液とし、4.5〜3.5g/m
inのスプレー速度でタンジェンシャル(サイド)スプ
レー様式にて500gの噴霧を行った時点で造粒を終了
し、本発明造粒品III を得た。このときのスプレー空気
量は30〜26L/min、出口空気温度は27〜26
℃であり、断熱飽和温度よりも4℃高い条件とした。本
発明造粒品III の平均粒子径(d50)は40μmであ
り、結合剤の造粒品中含量は約4.5重量%であった。
また、100μm以下の造粒粒子が約97%であった。Example 3 Finely pulverized diclofenac sodium particles (average particle size: 5
Aerosil # 200 (manufactured by Nippon Aerosil Co., Ltd.) corresponding to an amount of 2% by weight based on 500 g) was added to a tumbling fluidized bed granulator Agromaster (manufactured by Hosokawa Micron Corporation). 12 ~ heated to 60 ° C
While blowing an air amount of 15 m 3 / hr into the fluidized bed, the disk rotor was rotated at a rotation speed of 300 rpm at the bottom to roll and flow the powder. The composition of the spray liquid is Koll
A 5% by weight aqueous solution of idon 25, 4.5 to 3.5 g / m
The granulation was completed at the point of time when 500 g of the tangential (side) spray was sprayed at a spray rate of "in" to obtain a granulated product III of the present invention. The spray air amount at this time is 30 to 26 L / min, and the outlet air temperature is 27 to 26 L / min.
° C and 4 ° C higher than the adiabatic saturation temperature. The average particle size (d 50 ) of the granulated product III of the present invention was 40 μm, and the content of the binder in the granulated product was about 4.5% by weight.
Further, about 97% of the granulated particles had a size of 100 μm or less.
【0038】比較例1 局方ジクロフエナクナトリウムを粉砕することにより得
たジクロフエナクナトリウム微粉砕粒子(平均粒子径5
μm以下)500gに対して0.62重量%相当の量に
あたるアエロジル#200(日本アエロジル工業(株)
製)を添加し、転動流動層造粒装置アグロマスター(ホ
ソカワミクロン(株)製)に投入し、60℃に加温した
12〜17m3 /hrの空気量を流動層内に送風しなが
ら底部で300rpmの回転速度でディスクローターを
回転し粉体を転動、かつ流動させた。スプレー液の組成
はHPC−SSL8重量%水溶液と5重量%水溶液と
し、4.5〜5g/minのスプレー速度で順次各々1
00g、1000gの噴霧をタンジェンシャル(サイ
ド)スプレー様式にて行った時点で造粒を終了し比較造
粒品Iを得た。このときのスプレー空気量は35L/m
in、出口空気温度は32〜28℃であり、断熱飽和温
度よりも4〜7℃高い条件とした。比較造粒品Iの平均
粒子径(d50)は54μmであり、結合剤の造粒品中含
量は約10重量%であった。また、100μm以下の造
粒粒子が約95%であった。Comparative Example 1 Finely pulverized diclofenac sodium particles (average particle size: 5)
Aerosil # 200 (Nippon Aerosil Industry Co., Ltd.), equivalent to 0.62% by weight based on 500 g
Manufactured by Hosokawa Micron Co., Ltd.), and an air volume of 12 to 17 m 3 / hr heated to 60 ° C. is blown into the fluidized bed, and the bottom portion is formed. Then, the disk rotor was rotated at a rotation speed of 300 rpm to roll and flow the powder. The composition of the spray liquid is an 8% by weight aqueous solution of HPC-SSL and a 5% by weight aqueous solution.
At the time when the spraying of 00 g and 1000 g was performed in the tangential (side) spray mode, the granulation was completed and a comparative granulated product I was obtained. The spray air volume at this time is 35 L / m
In, the outlet air temperature was 32 to 28 ° C., which was 4 to 7 ° C. higher than the adiabatic saturation temperature. The average particle size (d 50 ) of the comparative granulated product I was 54 μm, and the content of the binder in the granulated product was about 10% by weight. Further, about 95% of the granulated particles had a size of 100 μm or less.
【0039】比較例2 局方ジクロフエナクナトリウムを粉砕することにより得
たジクロフエナクナトリウム微粉砕粒子(平均粒子径5
μm以下)500gに対して2重量%相当の量にあたる
アエロジル#200(日本アエロジル工業(株)製)を
添加し、転動流動層造粒装置スピロコータ(岡田精工
(株)製)に投入し、60℃に加温した12m3 /hr
の空気量を流動層内に送風しながら150rpmの回転
速度でディスクローターを回転し粉体を転動、かつ流動
させた。スプレー液の組成はHPC−SSL5重量%水
溶液とし、5g/minのスプレー速度でトップスプレ
ー様式にて1100gの噴霧を行い、比較造粒品IIを得
た。このときのスプレー空気量は30〜35L/mi
n、出口空気温度は36〜37℃であり、断熱飽和温度
よりも4〜5℃高い条件とした。比較造粒品IIの平均粒
子径は100μmであり、結合剤の造粒品中含量は約1
0重量%であった。Comparative Example 2 Finely pulverized diclofenac sodium particles (average particle size: 5)
Aerosil # 200 (manufactured by Nippon Aerosil Co., Ltd.) equivalent to 2% by weight based on 500 g) was added to a tumbling fluidized bed granulator Spirocoater (manufactured by Okada Seiko Co., Ltd.). 12m 3 / hr heated to 60 ° C
While blowing the amount of air into the fluidized bed, the disk rotor was rotated at a rotation speed of 150 rpm to roll and flow the powder. The composition of the spray liquid was a 5% by weight aqueous solution of HPC-SSL, and 1100 g of the liquid was sprayed in a top spray mode at a spray rate of 5 g / min to obtain a comparative granulated product II. The spray air amount at this time is 30 to 35 L / mi.
n, the outlet air temperature was 36 to 37 ° C., which was 4 to 5 ° C. higher than the adiabatic saturation temperature. The average particle size of the comparative granulated product II was 100 μm, and the content of the binder in the granulated product was about 1
It was 0% by weight.
【0040】本発明造粒品I〜III はいずれも低結合性
結合剤(HPC−SSL、PVP Kollidon 25)の造粒
品中含量が5重量%以下で平均粒子径が50μm以下の
微細な造粒粒子であり、特に本発明造粒品IIにおいては
走査型電子顕微鏡(Nireco(株)製)による電顕像から
1次粒子の微細な集合体であることが示唆され、空気の
流れ等の物理的要因で容易に1次粒子に崩壊、分散する
ことが予想された。即ち、造粒時のパルスジェットエア
ーによる分散機構により、微細な1次粒子があまり転動
圧密作用を受けないで弱い結合力で成り立っている集合
体であり、1次粒子への崩壊、分散には効果的であるこ
とが示唆された。Each of the granulated products I to III of the present invention is a fine granulated product in which the content of the low binding binder (HPC-SSL, PVP Kollidon 25) in the granulated product is 5% by weight or less and the average particle size is 50 μm or less. In particular, in the granulated product II of the present invention, a scanning electron microscope (manufactured by Nireco Corp.) electron microscopic image suggests that it is a fine aggregate of primary particles. It was expected that physical factors could easily cause the primary particles to collapse and disperse. That is, due to the dispersion mechanism by pulse jet air at the time of granulation, the fine primary particles are aggregates formed by a weak binding force without receiving much rolling consolidation action, and are disintegrated and dispersed into primary particles. Was suggested to be effective.
【0041】試験例1 本発明造粒品I〜III および比較造粒品I〜IIについ
て、乾式で(吸込み)風量30L/minのもとでレー
ザー型粒度分布測定器(LMS−30/乾式ユニット、
セイシン企業(株)製)を用いて崩壊、分散した粒子の
粒径を測定することにより、造粒品の1次粒子への崩
壊、分散性の容易さを評価した。その結果を表1に示
す。Test Example 1 For the granulated products I to III of the present invention and the comparative granulated products I to II, a laser type particle size distribution analyzer (LMS-30 / dry unit) was used in a dry manner (inlet) at an air volume of 30 L / min. ,
The ease of disintegration and dispersibility of the granulated product into primary particles was evaluated by measuring the particle size of the disintegrated and dispersed particles using a Seishin Enterprise Co., Ltd.). Table 1 shows the results.
【0042】[0042]
【表1】 [Table 1]
【0043】表1の結果から明らかなように、1次粒子
への崩壊、分散の程度は、本発明造粒品I〜III は優れ
ており、本試験の条件下で30%以上の1次粒子(10
μm以下)への崩壊、分散性がみられ、本発明造粒品の
有用性が示唆された。これに対し、比較造粒品I〜IIで
は1次粒子への崩壊、分散の程度が劣っており、比較造
粒品では吸入過程で造粒品が崩壊、分散し、吸入されて
肺へ到達することは困難であることが示唆された。As is evident from the results in Table 1, the granules I to III of the present invention are excellent in the degree of disintegration and dispersion into primary particles, and the primary granules of the present invention exhibit a primary degree of 30% or more under the conditions of this test. Particles (10
(μm or less) and dispersibility, indicating the usefulness of the granulated product of the present invention. On the other hand, the comparative granulated products I to II are inferior in the degree of disintegration and dispersion into primary particles, and the comparative granulated products disintegrate and disperse in the inhalation process, are inhaled and reach the lungs. It was suggested that it would be difficult to do so.
【0044】試験例2 ラット(SD系雄性ラット、約250g、チャールスリ
バー(株)製)を用いて本発明造粒品I及びIIのそれぞ
れ1mgを気道上部に投与し、HPLC法で血中濃度を
測定したところ、図1に示すように血中に高いレベルの
薬物を検出することができた。このことより本発明造粒
品は、経肺吸入用製剤として有用であると考えられた。
HPLCの条件は、カラム Chemcosorb 5-ODS-H (4.6×
250mm 、ケムコ(株)製)、アセトニトリル−0.1M
酢酸ナトリウム(35/65,V/V)pH6.3溶出溶
媒、2.8ml/min流速、280nmUV検出波長
である。Test Example 2 Using a rat (SD male rat, about 250 g, manufactured by Charles River Co., Ltd.), 1 mg of each of the granules I and II of the present invention was administered to the upper respiratory tract, and the blood concentration was determined by HPLC. As a result, as shown in FIG. 1, a high level of drug could be detected in the blood. Thus, the granulated product of the present invention was considered to be useful as a preparation for transpulmonary inhalation.
HPLC conditions were column Chemcosorb 5-ODS-H (4.6 ×
250mm, manufactured by Chemco Co., Ltd.), acetonitrile-0.1M
Sodium acetate (35/65, V / V) pH 6.3 Elution solvent, 2.8 ml / min flow rate, 280 nm UV detection wavelength.
【0045】[0045]
【発明の効果】本発明により、粒径分布がシャープでハ
ンドリング性に優れ、かつ1次粒子への崩壊、分散性の
良好な微細な造粒粒子を含む経肺吸入用製剤が提供され
る。Industrial Applicability According to the present invention, there is provided a preparation for transpulmonary inhalation containing fine granulated particles having a sharp particle size distribution, excellent handling properties, and good disintegration and dispersibility into primary particles.
【図1】図1は、本発明造粒品をラットの気道上部に吸
入投与したときの血中濃度の推移を示す。FIG. 1 shows changes in blood concentration when the granulated product of the present invention is inhaled into the upper respiratory tract of rats.
Claims (10)
の1次粒子とし、これに結合剤を用いてコーティングし
つつ造粒して得られる、吸入過程で1次粒子への崩壊、
分散性を示す平均粒子径が50μm以下の微細な造粒粒
子を含むことを特徴とする経肺吸入用製剤。Claims: 1. Particles containing an active ingredient are made into primary particles having a particle size of 10 μm or less, and are granulated while being coated with a binder.
A preparation for transpulmonary inhalation, comprising fine granulated particles having an average particle diameter of 50 μm or less exhibiting dispersibility.
びパルスジェットエアー等の分散機構のいずれかを含む
多機能型装置を用いて得られたものであることを特徴と
する請求項1記載の経肺吸入用製剤。2. The method according to claim 1, wherein the granulation step is performed by using a multifunctional apparatus including any of a dispersing mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air. The preparation for pulmonary inhalation according to claim 1.
0℃下で3.0センチポイズ以下のものであり、得られ
る造粒粒子中に占める結合剤含量が5重量%以下である
ことを特徴とする請求項1又は2記載の経肺吸入用製
剤。3. The method according to claim 1, wherein the binder has a viscosity of 2% by weight in an aqueous solution.
3. The preparation for transpulmonary inhalation according to claim 1 or 2, wherein the preparation has a viscosity of not more than 3.0 centipoise at 0 ° C and the binder content in the obtained granulated particles is not more than 5% by weight.
またはポリビニルピロリドンである請求項1〜3いずれ
か記載の経肺吸入用製剤。4. The preparation for pulmonary inhalation according to claim 1, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone.
粒粒子が経肺吸入用デバイスに装填されてなる経肺吸入
用製剤。5. A transpulmonary inhalation preparation comprising the granulated particles according to claim 1 loaded in a pulmonary inhalation device.
ター形式を含む)の1種以上を伴う複合型流動層装置を
用い、主薬を含む粒子径が10μm以下の1次粒子に、
結合剤を含むスプレー液を噴霧して該1次粒子をコーテ
ィングしつつ造粒を行い、吸入過程で1次粒子への崩
壊、分散性を示す平均粒子径が50μm以下の微細な造
粒粒子とすることを特徴とする、該造粒粒子を含む経肺
吸入用製剤の製造方法。6. Use of a composite fluidized bed apparatus involving at least one of rolling, centrifuging, stirring, and jetting (including a Wurster type) to form primary particles having a particle diameter of 10 μm or less containing a main ingredient,
Spraying a spray liquid containing a binder, granulating while coating the primary particles, disintegrating into primary particles in the inhalation process, fine granulated particles having an average particle size of 50 μm or less showing dispersibility. A method for producing a transpulmonary inhalation preparation containing the granulated particles.
びパルスジェットエアー等の分散機構のいずれかを含む
多機能型装置を用いることを特徴とする請求項6記載の
製造方法。7. The method according to claim 6, wherein in the granulation step, a multifunctional device including any of a dispersing mechanism such as rolling, centrifuging, stirring, jetting, and pulse jet air is used.
0℃下で3.0センチポイズ以下のものであり、得られ
る造粒粒子中に占める結合剤含量が5重量%以下である
ことを特徴とする請求項6又は7記載の製造方法。8. The composition according to claim 1, wherein the binder is a 2% by weight aqueous solution.
8. The method according to claim 6, wherein the granulated particles have a binder content of not more than 3.0 centipoise at 0 ° C. and not more than 5% by weight.
またはポリビニルピロリドンである請求項6〜8いずれ
か記載の製造方法。9. The method according to claim 6, wherein the binder is hydroxypropylcellulose or polyvinylpyrrolidone.
する工程をさらに含むことを特徴とする請求項6〜9い
ずれか記載の製造方法。10. The method according to claim 6, further comprising a step of loading the granulated particles into a device for transpulmonary inhalation.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3846197A JPH10218763A (en) | 1997-02-05 | 1997-02-05 | Transpulmonary inhalation preparation and its production |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3846197A JPH10218763A (en) | 1997-02-05 | 1997-02-05 | Transpulmonary inhalation preparation and its production |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH10218763A true JPH10218763A (en) | 1998-08-18 |
Family
ID=12525903
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3846197A Pending JPH10218763A (en) | 1997-02-05 | 1997-02-05 | Transpulmonary inhalation preparation and its production |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH10218763A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003077886A1 (en) * | 2002-03-20 | 2003-09-25 | Hosokawa Micron Corporation | Method of manufacturing chemical-containing composite particles |
JP2004262810A (en) * | 2003-02-28 | 2004-09-24 | Hosokawa Funtai Gijutsu Kenkyusho:Kk | Method for producing medicine-containing composite fine particle and transpulmonary preparation |
WO2007126063A1 (en) * | 2006-04-28 | 2007-11-08 | Lion Corporation | Granulated particle, tablet and method for producing granulated particle |
JP2008013480A (en) * | 2006-07-05 | 2008-01-24 | Sawai Pharmaceutical Co Ltd | Drug-containing micro-particle and method for producing the same |
EP1982703A2 (en) | 2007-04-19 | 2008-10-22 | FUJIFILM Corporation | A transpulmonary composition |
JP2013216610A (en) * | 2012-04-09 | 2013-10-24 | Showa Yakuhin Kako Kk | Method for producing formulation |
-
1997
- 1997-02-05 JP JP3846197A patent/JPH10218763A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003077886A1 (en) * | 2002-03-20 | 2003-09-25 | Hosokawa Micron Corporation | Method of manufacturing chemical-containing composite particles |
JP2004262810A (en) * | 2003-02-28 | 2004-09-24 | Hosokawa Funtai Gijutsu Kenkyusho:Kk | Method for producing medicine-containing composite fine particle and transpulmonary preparation |
WO2007126063A1 (en) * | 2006-04-28 | 2007-11-08 | Lion Corporation | Granulated particle, tablet and method for producing granulated particle |
JP2008013480A (en) * | 2006-07-05 | 2008-01-24 | Sawai Pharmaceutical Co Ltd | Drug-containing micro-particle and method for producing the same |
EP1982703A2 (en) | 2007-04-19 | 2008-10-22 | FUJIFILM Corporation | A transpulmonary composition |
JP2013216610A (en) * | 2012-04-09 | 2013-10-24 | Showa Yakuhin Kako Kk | Method for producing formulation |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100567645B1 (en) | Methods and systems for processing dispersible derivatives | |
JP7085538B2 (en) | Antifungal dry powder | |
JP4728558B2 (en) | Method for producing nanoparticles | |
JP2011068668A (en) | Microparticle and its therapeutic or diagnostic use | |
TW200817047A (en) | Drug microparticles | |
JP2007530465A (en) | Highly breathable insulin microparticles | |
JP6166859B2 (en) | Taste-masked active pharmaceutical powder composition and method for producing the same | |
WO1999027911A1 (en) | Soft-pellet drug and process for the preparation thereof | |
Kwok et al. | Formation of protein nano-matrix particles with controlled surface architecture for respiratory drug delivery | |
JP2010528094A (en) | Surface-modified aerosol particles, methods and apparatus for their production, and powders and dispersions containing these particles | |
JP2001508792A (en) | Novel formulation for inhalation having a flow bulk density of 0.28 to 0.38 G / ML containing formoterol | |
CN108463213A (en) | The preparation of inhalable zafirlukast particle | |
WO2003077886A1 (en) | Method of manufacturing chemical-containing composite particles | |
JP2021522161A (en) | Antifungal formulation for intrapulmonary administration containing itraconazole | |
JP6850524B2 (en) | Dry powder formulation for inhalation | |
JP2000507568A (en) | Spray-dried microparticles as therapeutic vehicles for gene therapy | |
US20100143331A1 (en) | Method for mixing powders | |
EP1311243A2 (en) | Process for the production and use of powdered mannitol and mannitol-containing compositions | |
Kundawala et al. | Influence of formulation components on aerosolization properties of isoniazid loaded chitosan microspheres | |
Park et al. | Surface modification strategies for high-dose dry powder inhalers | |
JPH10218763A (en) | Transpulmonary inhalation preparation and its production | |
JP4707937B2 (en) | Method for producing drug-containing composite particles and transpulmonary preparation | |
JP2008533055A (en) | Inhalant | |
GB1569611A (en) | Pelletised or granular medicament formulation | |
Buttini et al. | Back to basics: The development of a simple, homogenous, two‐component dry‐powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers |