JP6721629B2 - 肺使用のための高服用量のレボドパを含むカプセル - Google Patents
肺使用のための高服用量のレボドパを含むカプセル Download PDFInfo
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- JP6721629B2 JP6721629B2 JP2018102474A JP2018102474A JP6721629B2 JP 6721629 B2 JP6721629 B2 JP 6721629B2 JP 2018102474 A JP2018102474 A JP 2018102474A JP 2018102474 A JP2018102474 A JP 2018102474A JP 6721629 B2 JP6721629 B2 JP 6721629B2
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Description
本願は、2012年11月9日に出願された米国仮特許出願第61/724,781号、2013年9月30日に出願された米国仮特許出願第61/884,319号、同じく2013年9月30日に出願された米国仮特許出願第61/884,315号、および同じく2013年9月30日に出願された米国仮特許出願第61/884,436号の利益を主張する。本願は、現在は米国特許第8,545,878号となった2012年11月16日に出願された米国特許出願第13/679,245号の一部継続出願であり、2013年7月18日に出願された米国特許出願第13/945,160号の一部継続出願である。上記の出願の教示の全部は参照することにより本願に援用される。
daer=dg√ρtap
から計算され得る。式中、dgは幾何学的粒径(例えばMMGD)であり、ρは粉末密度である。
実施例1
この実施例では、本明細書では「90:8:2」と呼称される90:8:2のレボドパ:ジパルミトイルホスファチジルコリン(DPPC):塩化物(NaCl)組成物を生成するための噴霧乾燥動作に対して実施された改変例を調査するための一連の研究についてまとめられる。レボドパを含む粉末の初期ロットを生成するために開発された90:8:2噴霧乾燥動作は、約4%の含水量、5.4ミクロンより小さい50〜60%の範囲の微粒子割合、およびサイズ00カプセルあたり約23mgの最大カプセル充填重量を有する完全に非晶質である90:8:2レボドパ:DPPC:NaCl粉末の生成を伴った。特性のこの組み合わせにより、供給された最大レボドパ服用量(レボドパの微粒子量)は約12mgであった。なおこれらの粉末は、高い静電気帯電と、低いバルク密度(通常0.01〜0.02g/cc)と、タップ密度(通常0.02〜0.04g/cc)とを示した。これにより、これらの粉末をサイズ00カプセルに再現性をもって充填することは極めて困難なものとなった。これに基づいて、単位カプセルあたり供給されるレボドパ服用量を17mg以上に増加させるよう試みることが望まれた。加えて90:8:2粉末の物理的安定性を増大させることも望まれた。なぜなら、いくつかの粉末ロットは、特に実験室湿度が制御されない状態で充填されたロットに対して、保管時に非晶質−結晶質変換が生じ、その結果、これらのロットが高い湿度にさらされる可能性が生じたことが観察されたからである。
3種類の変更すなわち(1)ユニット動作変更と、(2)プロセスパラメータ変更と、(3)調合変更と、が評価された。
2種類のユニット動作変更すなわち(i)加湿パージガスと、(ii)インライン・イオン化と、についての研究がなされた。静電気的帯電の低下と、カプセルの最大充填重量の増加と、に関して、これら2つのうち加湿パージガスの使用が最善の結果を示した。この変更の詳細について以下で説明する。
パージガスは異なる相対湿度レベルに加湿された。パージガス流入口に対する回転流量計は3.5g/分または20scfhに設定された。
標準的構成
異なるRHに加湿された窒素パージガスを使用して生成された粉末が、0%の相対湿度の標準的パージガス条件下で製造された粉末と対比して同様の粒径および微粒子割合を有することが観察された(表1)。
パージガスの加湿により、FPFおよび含水量が同一に保持される一方で粉末が稠密化されることが観察されたが、これらの調合は、いくつかの場合では、特に10%を越えるパージガス加湿に対して、XRPDによる結晶相の形成の証拠を示すことが観察された。結果として、10%RHを越えて加湿されたパージガスの使用は、実行可能な選択肢ではないことが判定された。なお5〜10%の範囲のパージガス相対湿度を使用することにより、粉末の静電気的帯電の軽減と、粉末FPFの減少または非晶質−結晶質変換を生じさせることなく粉末密度の増大と、をもたらすための機構が提供された。
90:8:2のレボドパ:DPPC:NaCl粉末に対する代替的な調合が、FPF、充填重量、および固体安定性の最適化における有効性に関して評価された。
DPPC:NaClの代替的な比を有する粉末が、90%レボドパ粉末の密度の増大化および静電気的帯電の低減化における効率に関して評価された。粉末の塩含有量の増大化が粉末の静電気的帯電を解消させ、それにより静電気的帯電を低減させることを支援するよう機能するのではないかという仮説が立てられた。
4:6のDPPC:NaCl比が当初、多量の塩化ナトリウムが90:8:2粉末のFPFおよび密度に対して及ぼす影響を評価するための開始点として選択された。パージガス相対湿度が0%および10%の両方に維持された。
これらの結果に基づいて、5:5のDPPC:NaCl比も生成および分析された。この調合の3回の実行に対する微粒子割合、バルク密度/タップ密度、および幾何学的粒径を以下の表7にまとめる。
賦形剤または賦形剤の代表品の添加も、90:8:2粉末のFPMおよびバルク密度の最適化に向かう潜在的な経路として調査された。賦形剤であるL−ロイシン、クエン酸ナトリウム、および塩化カルシウム(これらは組織内で入手可能である)が、添加物として、または現在の90:8:2のレボドパ:DPPC:NaCl調合における賦形剤の代表品として、使用および評価された。
クエン酸ナトリウムが塩化ナトリウムに対する潜在的な代替物として評価され、塩化カルシウムが、現在の調合に対する他の潜在的な塩添加物として調査され、L−ロイシンがDPPCに対する潜在的な代替物として評価された。塩化カルシウムが使用されたとき、レボドパの量は90%から50%に減少された。噴霧乾燥されるための溶液に対する固体濃度は1g/Lに維持された。
L−ロイシンの添加により粉末のタップ密度およびバルク密度は大きくなったが、FPFは、標準的な90:8:2のレボドパ:DPPC:NaCl調合のFPFよりも顕著に小さくなった。
標準的な90:8:2調合粉末は高い静電気的帯電を有する低密度粉末である。低密度90:8:2粉末が大きい体積を占有するため、その空気力学的性能を影響することなくカプセル内に充填され得る粉末の量は大きく制限される。係る低密度粉末が高い静電気的帯電を有する場合、帯電した粉末がカプセルおよび充填用機材の壁部と常に相互作用することにより、カプセルの充填重量に高程度の変動性が見られ得る。係る粉末に対するカプセル充填動作(同時に低い充填重量と高い重量変動とを示す)は、一連の特異的な難題を提示した。これらの難題の全部は、充填機材の変更を必要とした。係る変更は、粉末の物理的特性および化学的特性に影響を及ぼすことなく充填重量目的の達成を支援した。
この真空構成では、Gast真空ポンプ(モデル#1023−101Q−G608X)が、KFM機械に搭載された真空に代わって、投与器に対する真空として使用された。
(i)90:4:6のレボドパ:DPPC:NaClを含む、標準的なサイズ00の真空投与器と、
(ii)90:8:2のレボドパ:DPPC:NaClを含む、標準的なサイズ00真空投与器と、
(iii)90:5:5のレボドパ:DPPC:NaClを含む、標準的なサイズ00真空投与器と、
(iv)90:8:2のレボドパ:DPPC:NaClを含む、全内径サイズ00の真空投与器と、
(v)ラクトース1水和物NFを含む、全内径サイズ00の真空投与器、サイズ4プランジング投与器、およびサイズ5プランジング投与器と、
を含んだ。
この実験に対して、標準的サイズ00投与器が、90:4:6のレボドパ:DPPC:NaCl調合を噴霧乾燥することにより得られた粉末を充填するために使用された。この実験において充填重量精度に関して評価された変量は、(i)粉末床に対する水平ブレード体プラットフォーム、および(ii)低対高の粉末床高さ、を含んだ。この実験に対する結果を以下の表9にまとめる。
この実験では、標準的なサイズ00投与器が90:8:2のレボドパ:DPPC:NaCl調合を充填するために使用された。充填重量精度に対して評価された変量は、(i)低粉末床高さ、(ii)粉末床における粉末を分冊するためにブレードおよびレーキの使用、および(iii)高対低の投与器真空、を含んだ。この実験に対する結果を表10にまとめる。
この実験では、標準的なサイズ00投与器が90:5:5のレボドパ:DPPC:NaCl調合を充填するために使用された。この実験では、1つのみの変量、すなわち低い投与器真空対高い投与器真空、が充填重量精度に対して評価された。この実験に対する結果を以下の表11にまとめる。
ここで図4を参照すると、全内径投与器20は、標準的な投与器チャンバの通常の内径である0.250インチと比較して、メッシュスクリーン26における投与器チャンバの内径が0.286インチに増大化されるよう変更された標準的真空投与器である。投与器20は、図5に示すように、投与器プランジャ22が静止状態に留まり、真空を印加することにより粉末が投与器20内に引き込まれ、噴出圧力を印加することにより粉末が投与器20から排出されるようにも、変更された。真空は適切な配管を用いてポート24において投与器20に取り付けられたポンプにより生成された。粉末が定位置を越えて侵入し真空ポンプおよび配管と干渉することを防止するために、2ミクロンのメッシュスクリーン26がプランジャ22の底部に追加された。噴出圧力は外部貯蔵タンクから加圧された窒素源により提供された。
通常、多量粉末の充填は肺用製品に対しては一般的ではない。出願者らは、経肺供給用のカプセルに多量の粉末を充填することを可能にする新規パラメータおよび処理を特定した。90:8:2の活性粉末に対して、外部真空により支援されるサイズ00全内径真空投与器は、90:8:2粉末に対して見られた23mgの以前の最大充填重量と比較して、より高い最大充填重量(最大で38mg以上)と、KFM III−Cカプセル充填機械上での精度および再現可能性を有する充填重量と、を達成するために使用され得る。
特定種類のカプセルが放出される粉末の服用量を増加させる上で有用ではないかという仮説が立てられた。HPMC「透明」カプセルとHPMC/二酸化チタン「白色」カプセルが選択された。放出服用量管で構成された吸入器を有する2つの作業台が提供された。透明または白色のカプセルが、実質例1により目標装填量まで調合され吸入器内に配置された吸入可能レボドパ粉末(レボドパ:DPPC:NaClが90:8:2の乾燥重量比)で28mgまで充填された。分析者が各ステーションに割り当てられ、28.3L/分で4.2秒間にわたり吸入器をEDチューブに作動させ、内容物を洗滌した。内容物のFPFが標準的な手順を使用して測定された。分析者は、作業台を切り替え、それぞれ他の吸入器技法を使用した。結果を以下の表13〜表20に示す。表13および表14は、透明カプセル(二酸化チタンを含まない)と、シオノギ製の白色カプセルと、の比較を示す。表15および表16は、同一研究を示すが、分析者は作業台を切り替えて、それぞれ他の吸入器技法を使用した。表17および表18は、表13〜表16の結果の編集である。表19および表20は透明カプセル(二酸化チタンを含まない)と、Capsugel社製の白色カプセルと、の比較を示す。
カプセル物質に二酸化チタンを含まない透明カプセルから放出された粉末と比較して、より多量の粉末が、HPMCおよび二酸化チタンを含むカプセル物質を有する白色カプセルから放出されたことが、データにより示される。このデータは驚くべきである。いかなる理論にも限定されるものではないが、カプセル物質中に存在する二酸化チタンが、カプセルから放出する際にカプセル壁部に固着する粉末の量を減少させたものと考えられる。
目的
重量測定ACI−3およびXRPDを使用して75%の相対湿度および25℃に15分間、30分間、および60分間曝露された機械充填されたカプセル内の90/8/2および90/5/5のレボドパ粉末を特徴付けること。追加的な時間ポイントが曝露の240分および360分において加えられ、白色カプセルおよび透明カプセルはロット41021(90/8/2)を用いてテストされた。
1.物質
・白色および透明のHPMCカプセルに封入された手動充填90%L−ドパ
1回の引き込みあたり4カプセル
・ロット41018で充填された
2.テストスケジュール
・カプセルは以下の表23に列挙した時間にわたり25℃/75%RHチャンバに保管される。カプセルは、曝露の間カプセルキャップが装着された状態で、各種類のカプセルに対して曝露の間キャップが装着されない状態で、テストされる。
Claims (12)
- 吸入装置において使用されるためのカプセルであって、前記カプセルはレボドパ、リン脂質及び塩を含む乾燥粉末で充填され、前記乾燥粉末は0.01g/cm 3 〜0.1g/cm 3 の範囲の作業密度を有し、前記カプセルのシェルはヒドロキシプロピルメチルセルロース(HPMC)および二酸化チタンを含む、カプセルにおいて、
前記乾燥粉末は75重量%以上のレボドパを含み、
吸入装置からの前記乾燥粉末の作動時に、前記乾燥粉末の放出された用量は、50%〜65%のFPF(5.6)(5.6μm未満の空気力学的粒径を有する微粒子割合)を有する、カプセル。 - 吸入装置からの前記乾燥粉末の作動時に、前記乾燥粉末の放出された用量は、50%〜55%のFPF(5.6)を有する、請求項1に記載のカプセル。
- 前記乾燥粉末は2〜8重量%の水分を含む、請求項1に記載のカプセル。
- 前記乾燥粉末は5〜6重量%の水分を含む、請求項3に記載のカプセル。
- 前記カプセルは00サイズカプセルである、請求項1に記載のカプセル。
- 前記乾燥粉末は15〜50ミリグラムのレボドパを含む、請求項5に記載のカプセル。
- 前記乾燥粉末は25〜35ミリグラムのレボドパを含む、請求項6に記載のカプセル。
- 前記塩は塩化ナトリウムである、請求項1に記載のカプセル。
- 前記リン脂質はジパルミトイルホスファチジルコリン(DPPC)である、請求項1に記載のカプセル。
- 前記乾燥粉末はDPPCおよび塩化ナトリウムをさらに含む、請求項1に記載のカプセル。
- 前記乾燥粉末の前記FPFは名目上の服用量の50〜70%である、請求項1に記載のカプセル。
- 前記カプセルは30〜50ミリグラムの前記乾燥粉末で充填された、請求項1に記載のカプセル。
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US13/679,245 US8545878B1 (en) | 2012-11-09 | 2012-11-16 | Capsules containing high doses of levodopa for pulmonary use |
US13/679,245 | 2012-11-16 | ||
US13/945,160 | 2013-07-18 | ||
US13/945,160 US8685442B1 (en) | 2012-11-09 | 2013-07-18 | Capsules containing high doses of levodopa for pulmonary use |
US201361884436P | 2013-09-30 | 2013-09-30 | |
US201361884319P | 2013-09-30 | 2013-09-30 | |
US201361884315P | 2013-09-30 | 2013-09-30 | |
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JP2015541916A Active JP6836834B2 (ja) | 2012-11-09 | 2013-11-08 | 乾燥粉末を含むカプセルを充填する投与装置 |
JP2015541917A Active JP6348501B2 (ja) | 2012-11-09 | 2013-11-08 | 超低密度肺粉剤 |
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