JP6324069B2 - 治療学的に有効な物質を含む加湿された粒子 - Google Patents
治療学的に有効な物質を含む加湿された粒子 Download PDFInfo
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Description
数多くの疾患及び臨床的状況においては、治療学的に有効な物質を患者の気道中へと導入し、前記物質を罹患した1以上の組織と直接的に接触させる(あらゆる可能性のある副作用を伴う全身投与を必要としない)か、又はその物質の安定性への潜在的な悪影響と所望の薬理効果の比較的遅い始まりを伴う胃腸系を迂回しつつ全身投与を実現するかのいずれかが望ましい。
本発明の課題は、医薬品活性(すなわち治療目的のために活用できる所望の活性)を有する粒子、特に肺サーファクタント及び/又は任意の他の治療学的に有効な物質を含む粒子であって、吸入により患者に投与することができ、かつ当該技術分野から公知の粒子の欠点の少なくとも幾つかを克服した粒子を提供することである。より具体的には、本発明の課題は、少なくとも1種の治療学的に有効な物質を含む吸入可能な粒子であって、吸入後に示される、患者の上部気道及び下部気道の内部にアグロメレート及び沈着物を形成する傾向が大きく低減されていることを特徴とする粒子を提供することである。
(a)少なくとも1種の治療学的に有効な物質を含む実質的に乾燥した吸入可能な粒子を提供するステップと、
(b)前記粒子をキャリヤーガス中に懸濁して、第一のエーロゾルを得るステップと、
(c)前記の第一のエーロゾルに水蒸気を添加して、前記の第一のエーロゾルよりも高い含水率を有する第二のエーロゾルを得るステップと、
(d)前記の第二のエーロゾルの温度及び/又は圧力を、該第二のエーロゾルの露点を下回って、粒子上に水の凝縮が生じるように調節するステップと、
によって得ることができる。
(i)第一のエーロゾルと水蒸気源とを接触させることか、又は
(ii)第一のエーロゾルと、水蒸気を含むガス又はガス混合物とを混合すること
のいずれかと、任意にステップ(i)又は(ii)の実施の前又はその間に前記のエーロゾルを加熱することによって達成される。
・ 患者の気道中での沈着及び塊の形成は低減されているか、又は完全に抑制されてさえもいるため、大きく向上した安全性を提供する。
(1)実質的に乾燥した吸入可能な粒子のエーロゾル化が可能なエーロゾル化ユニットと、
その際、該エーロゾル化ユニットは、キャリヤーガスの源に取り付け可能な入口と出口とを有する、
(2)入口と、加湿室と、出口とを含む加湿器と、
その際、前記の入口と出口とは、前記の加湿室を介して互いに流体流れ接続されており、前記の加湿室は、水蒸気の源を含んでいる、
(3)以下の
(3a)入口と少なくとも1つの出口とを有する患者インターフェイス、
その際、前記の患者インターフェイスは、前記の少なくとも1つの出口を介して、患者の気道へと加湿された粒子のエーロゾルの吸入による投与を可能にする、
又は
(3b)患者インターフェイスに接続可能なポート、
その際、前記のポートは、患者への吸入による投与のための前記の患者インターフェイスへと加湿された粒子のエーロゾルを運ぶことを可能にする、
のいずれかと、
(4)エーロゾル化ユニットの出口と、加湿器の入口とを接続する第一の導管と、
(5)加湿器の出口と、患者インターフェイスの入口又は患者インターフェイスに接続可能なポートとを接続する第二の導管と、
その際、前記の第二の導管は、前記のエーロゾルの温度及び/又は圧力の調整を可能にする
を含む。
(a)少なくとも1種の治療学的に有効な物質を含む実質的に乾燥した吸入可能な粒子を提供するステップと、
(b)前記のステップ(a)の粒子をキャリヤーガス中に懸濁して、第一のエーロゾルを得るステップと、
(c)前記の第一のエーロゾルに水蒸気を添加して、前記の第一のエーロゾルよりも高い含水率を有する第二のエーロゾルを得るステップと、
(d)前記の第二のエーロゾルの温度及び/又は圧力を、該第二のエーロゾルの露点を下回って、粒子上に水の凝縮が生じるように調節するステップと、
を含む前記方法である。
例1: 噴霧乾燥された肺サーファクタント粒子の製造
7.0gの1,2−ジパルミトイル−3−sn−ホスファチジルコリン(DPPC)と、2.5gの1−パルミトイル−2−オレオイル−3−sn−ホスファチジルグリセロールナトリウム(POPG−Na)と、205mgの塩化カルシウム二水和物と、250mgのパルミチン酸を、60℃に加熱された300mlの2−プロパノール/水(85:15)中に溶解した。前記溶液を20℃にまで冷却した後に、その溶液を、350mLの、rSP−C FF/I(INN:ルスプルチド)をクロロホルム/メタノール(9:1)中に溶かした溶液(c=429mg/L)と混合した。得られた溶液を、Buechi B 191型の噴霧乾燥装置を使用して噴霧乾燥させた。乾燥ガスは、乾燥室に入るときは90℃の空気であり、乾燥室を出るときは52℃〜54℃の空気であった。白っぽい緩い粉末が得られた。
図2で概説された構成を使用して、加湿された肺サーファクタント粒子を生成させた。これに対して、例1からの噴霧乾燥された肺サーファクタントであって、約2.5μmの平均幾何径を有するもの3グラムを、WO2006/108558から公知の装置と同様であるが、欧州特許出願EP09158625.5に開示される変更を有するエーロゾル化ユニットのレザバー中に装填した。サーファクタント粉末のエーロゾル化を達成するために、WO2006/108558に記載された、ソレノイドバルブを用いてパルス化されたキャリヤーガス(空気)の源を、エーロゾル化ユニットの遠位の取付部(入口)と、小さい滅菌グレードのフィルタを介して接続した。エーロゾル化ユニットの近位の取付部を、50mLの容量を有する小さいスペーサー(圧力パルスの減衰のための緩衝容量としてはたらく)に接続した。前記のスペーサーは、追加量の補助空気で一般に0.7L/分の流速で連続的にフラッシングした。前記の補助空気の流れを、前記のスペーサーの円筒部の壁部に沿ってシース流を形成する構成とした。こうして前記スペーサーに入るエーロゾル流が被鞘され、スペーサーの壁部上にエーロゾル化された粒子が沈積するのを避けることが効率的に補助される。
更なる特性決定のために、例2に記載したように製造された加湿された肺サーファクタント粒子を、動的水蒸気吸着実験と、レーザ回折分光実験とに供した。
等温動的水蒸気吸着実験において、一定温度で変動する度合いの相対湿度にさらされたサンプルの質量変化が測定される。肺サーファクタント粒子の吸水挙動の分析のために、CISorp社製の機器(CI Electronics, Marpire, France)を使用した。実験は、二重に行った。例1に従って得られた乾燥したサーファクタント粉末約10mgを、2つのガラス製の皿A及びBのそれぞれにおいて秤量した。前記のガラス製の皿を、試験室に入れて、該試験室内の相対湿度を、段階的に5%から95%へと調整し、次いで20%に戻した。温度は、試験全体の間、37℃に保った。サンプルへの水の吸着によって引き起こされる前記皿の質量変化を記録し、時間に対して(及び、相対湿度の変化に対して)プロットした。それらの実験は、調査された粒子が80%の相対湿度で約15%の質量増加を伴って吸湿性であることを示した(図5a)。また、80%の相対湿度の範囲において、水の取り込みは、実質的に可逆的であることも分かる(図5b)。
粒子の特性決定は、HELOS回折センサ(Sympatec, Clausthal-Zellerfeld, Germany)を使用して行った。このよく知られた回折法は、粒度分布のインサイチュー測定を可能にする。測定は、使用チューブ("第二の導管")の出口で直接的に、100%の相対湿度の気相で行うか、又は52cm長のアクリルガラスチューブ("乾燥チューブ"として用いられる)の出口で、100%をかなり下回る相対湿度で行った。加湿された粒子のエーロゾルを乾燥させるために、前記の使用チューブを出たエーロゾルを、前記の乾燥チューブに運び、乾燥空気と混合した。該混合物は、乾燥チューブ中を進むが、粒子表面上の水が蒸発して、より小さい粒子となる。この収縮は、サイズ分布のより小さい中央粒径(X50値)として検出できた。
図1:本発明による粒子の製造のために有用な装置のブロック図。
Claims (15)
- 肺サーファクタントを含む、乾燥質量の25%〜40%に相当する水膜によって覆われた粒子であって、以下のステップ:
(a)肺サーファクタントを含む実質的に乾燥した吸入可能な粒子を提供するステップと、
(b)前記ステップ(a)の粒子をキャリヤーガス中に懸濁して、第一のエーロゾルを得るステップと、
(c)前記の第一のエーロゾルに水蒸気を添加して、前記の第一のエーロゾルよりも高い含水率を有する第二のエーロゾルを得るステップと、
(d)前記の第二のエーロゾルの温度及び/又は圧力を、該第二のエーロゾルの露点を下回って、粒子上に水の凝縮が生じるように調節するステップと、
によって得ることができる前記粒子。 - 請求項1に記載の粒子であって、ステップ(c)における第一のエーロゾルに水蒸気を添加して、第二のエーロゾルを得ることは、
(i)第一のエーロゾルと水蒸気の源とを接触させることか、又は
(ii)第一のエーロゾルと、水蒸気を含むガス又はガス混合物とを混合すること
のいずれかと、任意にステップ(i)又は(ii)の実施の前又はその間に前記のエーロゾルを加熱することによって達成される前記粒子。 - 請求項2に記載の粒子であって、ステップ(i)における水蒸気の源は、半透性のバリヤーであり、かつ第一のエーロゾルへの水蒸気の添加は、第一のエーロゾルを加湿器の加湿室に流過させることによって達成され、前記加湿器は、加湿室中の第一のエーロゾルを水から37〜100℃の温度で第二の室において分離する前記半透性のバリヤーを特徴とし、その半透性のバリヤーは、第二の室から加湿室への、水蒸気の通過と、場合により熱の通過を可能にするが、液体の水の通過を遮断する前記粒子。
- 請求項1から3までのいずれか1項に記載の粒子であって、ステップ(d)において、第二のエーロゾルの露点を、該第二のエーロゾルの温度を第一の温度から第二の温度へと低下させることによって下回る前記粒子。
- 請求項4に記載の粒子であって、第二のエーロゾルの第一の温度が、45℃と75℃の間である、前記粒子。
- 請求項4又は5に記載の粒子であって、第二のエーロゾルの第二の温度が、18℃と40℃の間である、前記粒子。
- 請求項4から6までのいずれか1項に記載の粒子であって、ステップ(d)は、第二のエーロゾルが、ある流速で、装置内の予定された経路に沿って、より高い温度を有する領域からより低い温度を有する領域へと移動することを特徴としている前記粒子。
- 請求項7に記載の粒子であって、前記の予定された経路が、第二のエーロゾルが流過するチュービングによって定義されており、前記の第二のエーロゾルの温度の低下は、チュービングの内腔から、前記エーロゾルが前記チュービングに入るところの温度よりも低い温度にあるチュービングの外側への熱の正味流れによって達成され、前記チュービングは、円筒形又は円錐形であり、前記チュービングの長さは、40cmと140cmの間であり、かつ前記チュービングの内径は、1mmと5mmの間である前記粒子。
- 請求項7又は8に記載の粒子であって、前記の第二のエーロゾルの流速が、0.2〜6L/分である前記粒子。
- 請求項1から9までのいずれか1項に記載の粒子であって、第二のエーロゾルの、該エーロゾルの露点を下回るのに必要とされるステップ(d)における温度及び/又は圧力の調整が、0.1〜2秒にわたって行われる前記粒子。
- 治療において使用するための、請求項1から10までのいずれか1項に記載の粒子。
- 新生児呼吸窮迫症候群、未熟児の新生児呼吸窮迫症候群および後天性呼吸窮迫症候群を含む呼吸器系の疾患、慢性閉塞性肺疾患又は嚢胞性線維症の治療において使用するための、請求項1から10までのいずれか1項に記載の粒子。
- 肺サーファクタントを含む実質的に乾燥した吸入可能な粒子を含む組成物の、請求項1から12までのいずれか1項に記載の粒子の製造のための使用。
- 請求項1から10までのいずれか1項に記載の粒子の発生のための装置であって、前記装置は、
(1)実質的に乾燥した吸入可能な粒子のエーロゾル化が可能なエーロゾル化ユニットと、
その際、該エーロゾル化ユニットは出口を有し、適宜、入口を介してキャリヤーガスの源と流体流れ接続されている、
(2)入口と、加湿室と、出口とを含む加湿器と、
その際、前記の入口と出口とは、前記の加湿室を介して互いに流体流れ接続されており、前記の加湿室は、水蒸気の源を含んでいる、
(3)入口と少なくとも1つの出口とを有する患者インターフェイス、
その際、前記の患者インターフェイスは、前記の少なくとも1つの出口を介して、患者の気道へと加湿された粒子のエーロゾルの吸入による投与を可能にする、
(4)エーロゾル化ユニットの出口と、加湿器の入口とを接続する第一の導管と、
(5)加湿器の出口と、患者インターフェイスの入口とを接続する第二の導管と、
その際、前記の第二の導管は、前記の第二のエーロゾルの温度及び/又は圧力の調整を可能にする
を含む前記装置。 - 肺サーファクタントを含む、乾燥質量の25%〜40%に相当する水膜によって覆われた粒子のエーロゾルの発生方法であって、以下のステップ:
(a)肺サーファクタントを含む実質的に乾燥した吸入可能な粒子を提供するステップと、
(b)前記ステップ(a)の粒子をキャリヤーガス中に懸濁して、第一のエーロゾルを得るステップと、
(c)前記の第一のエーロゾルに水蒸気を添加して、前記の第一のエーロゾルよりも高い含水率を有する第二のエーロゾルを得るステップと、
(d)前記の第二のエーロゾルの温度及び/又は圧力を、該第二のエーロゾルの露点を下回って、粒子上に水の凝縮が生じるように調節するステップと、
を含む前記方法。
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