JP2006507218A - レボドパの肺送達 - Google Patents
レボドパの肺送達 Download PDFInfo
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- JP2006507218A JP2006507218A JP2003577824A JP2003577824A JP2006507218A JP 2006507218 A JP2006507218 A JP 2006507218A JP 2003577824 A JP2003577824 A JP 2003577824A JP 2003577824 A JP2003577824 A JP 2003577824A JP 2006507218 A JP2006507218 A JP 2006507218A
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- aqueous solution
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- NJGWOFRZMQRKHT-WGVNQGGSSA-N surfactin C Chemical compound CC(C)CCCCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1 NJGWOFRZMQRKHT-WGVNQGGSSA-N 0.000 description 1
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Abstract
Description
本出願は、2002年3月20日に提出した米国特許仮出願60/366,471号の利益を主張する。前記出願の全ての教示は、参照により本明細書に援用される。
パーキンソン病は、基底核中のドパミンニューロンの変性により神経病理学的に、そして消耗性の震え、動作の緩慢および平衡性の問題により神経学的に特徴づけられる。パーキンソン病を患う人は100万人を超えると推定される。ほとんど全ての患者は、ドパミン前駆物質レボドパまたはL−ドパを、しばしばドパ−デカルボキシラーゼインヒビター、カルビドパ(carbidopa)と組み合わせて受けている。L−ドパは、パーキンソン病の徴候をこの病気の初期の段階で適切に抑える。しかしながら、これは、この疾患の過程において、数ヶ月〜数年の間の期間後に効力を失う傾向がある。
本発明は、中枢神経系(CNS)の疾患を処置する方法に関する。より具体的には、本発明は、パーキンソン病を処置するのに適切な薬剤、たとえばレボドパを肺に送達するための粒子および方法に関する。
本発明の特徴および多の詳細は、本発明の段階または本発明の部分の組み合わせのいずれかとしてより詳しく記載され、特許請求の範囲で示される。本発明の特定の態様が図面により示され、本発明を限定するものではないことは理解されるだろう。本発明の本質的な特徴は、発明の範囲を逸脱することなく種々の態様で使用されるだろう。
還元糖よりも非還元糖の存在が、他の生物活性剤または薬剤(たとえば、カルビドパ、エピネフリンおよび他のカテコールアミンなど)を含む組成物のためにもなり得ることがさらに考えられる。
エピネフリン、アルブテロール、他のカテコールアミン、サルメテロール、ロピニロールおよびピロキシカンが挙げられる。さらに、90%以下の生物活性剤、たとえば、L−ドパを含む組成物は、また、前記のような塩を添加することによって利益を得る。
(式中、dgは、幾何学的直径、例えば、MMGDであり、ρは、粉末密度である)
によってエンベロープ球体直径、dに関係づけられる(Gonda,I. 「エーロゾル送達における物理−化学的原理(Physico-chemical principles in aerosol delivery) 」Topics in Pharmaceutical Sciences 1991(D.J.A.CrommelinおよびK.K.Midha 編)、pp.95〜117、Stuttgart:Medpharm Scientific Publishers、1992))。ヒト肺の肺胞領域における単分散エーロゾル粒子の最大限の沈着(約60%)は、約daer=3μmの空気力学的直径について起こる。Heyder,J. ら、J.Aerosol Sci.、17:811-825(1986)。その小さなエンベロープ質量密度により、最大深肺沈着を示す単分散吸入粉末を含む空気力学的に軽い粒子の実際の直径dは:
である。例えば、エンベロープ質量密度、ρ=0.1g/cm3を示す空気力学的に軽い粒子は、9.5 μmの大きさのエンベロープ直径を有する粒子について最大沈着を示す。粒子サイズが大きくなると、粒子間接着力が低下する。Visser,J.、Powder Technology、58:1-10。従って、大きな粒子サイズは、より低い食作用損失に寄与することに加えて、エンベロープ質量密度の低い粒子に関して深肺へのエーロゾル適用の効率を高める。
L-ドパを含有する乾燥粒子の調製
実施例1−L-ドパおよびトレハロースを含有する粒子
L-ドパおよびトレハロースを含有する製剤を含む粒子を、以下のようにして調製した。水溶液を、2.375 g L-ドパおよび125 mgトレハロースを700 mlのUSP水に添加することにより形成した。有機溶液は300 mlのエタノールから構成された。水溶液および有機溶液をスタティックミキサー中で合わせた。合わせた容量で合計1 Lを使用し、全溶質濃度は、30/70エタノール/水中2.5 g/Lであった。合わせた溶液はスタティックミキサーから2液アトマイザー内へと流れ、得られた霧化液滴を以下の処理条件下で噴霧乾燥した。
供給口温度 約135℃
乾燥ドラムからの排出口温度 約49〜53℃
窒素乾燥用ガス=95 kg/時
霧化速度=14 g/分
2液内部混合ノズルアトマイザー
液体供給速度=70 ml/分
乾燥チャンバ内の圧力=水中で-2.0
L-ドパ、トレハロースおよび塩化ナトリウムを含有する製剤を含む粒子を、以下のようにして調製した。水溶液を、2.325 g L-ドパ、125 mgトレハロースおよび50 mg塩化ナトリウムを700 mlのUSP水に添加することにより形成した。有機溶液は300 mlのエタノールから構成された。水溶液および有機溶液をスタティックミキサー中で合わせた。合わせた容量で合計1 Lを使用し、全溶質濃度は、30/70エタノール/水中2.5 g/Lであった。合わせた溶液はスタティックミキサーから2液アトマイザー内へと流れ、得られた霧化液滴を以下の処理条件下で噴霧乾燥した。
供給口温度 約135℃
乾燥ドラムからの排出口温度 約49〜53℃
窒素乾燥用ガス=95 kg/時
霧化速度=14 g/分
2液内部混合ノズルアトマイザー
液体供給速度=70 ml/分
液体供給温度 約50℃
乾燥チャンバ内の圧力=水中で-2.0
L-ドパおよびDPPCを含有する製剤を含む粒子を、以下のようにして調製した。水溶液を、1.1875 g L-ドパを300 mlのUSP水に添加することにより形成した。有機溶液は、700 mlのエタノール中の62.5 mg DPPCから構成された。水溶液および有機溶液をスタティックミキサー中で合わせた。合わせた容量で合計1 Lを使用し、全溶質濃度は、70/30エタノール/水中1.25 g/Lであった。合わせた溶液はスタティックミキサーから2液アトマイザー内へと流れ、得られた霧化液滴を以下の処理条件下で噴霧乾燥した。
供給口温度 約108℃
乾燥ドラムからの排出口温度 約49〜53℃
窒素乾燥用ガス=95 kg/時
霧化速度=18 g/分
2液内部混合ノズルアトマイザー
液体供給速度=70 ml/分
液体供給温度 約50℃
乾燥チャンバ内の圧力=水中で-2.0
L-ドパ、DPPCおよび塩化ナトリウムを含有する製剤を含む粒子を、以下のようにして調製した。水溶液を、1.125 g L-ドパおよび25 mg塩化ナトリウムを300 mlのUSP水に添加することにより形成した。有機溶液は、700 mlのエタノール中の100 mg DPPCから構成された。水溶液および有機溶液をスタティックミキサー中で合わせた。合わせた容量で合計1 Lを使用し、全溶質濃度は、70/30エタノール/水中1.25 g/Lであった。合わせた溶液はスタティックミキサーから2液アトマイザー内へと流れ、得られた霧化液滴を以下の処理条件下で噴霧乾燥した。
供給口温度 約108℃
乾燥ドラムからの排出口温度 約49〜53℃
窒素乾燥用ガス=95 kg/時
霧化速度=18 g/分
2液内部混合ノズルアトマイザー
液体供給速度=70 ml/分
液体供給温度 約50℃
乾燥チャンバ内の圧力=水中で-2.0
Claims (30)
- 患者の気道に、約90重量パーセントを超えるレボドパと、非還元糖、リン脂質およびそれらの任意の組み合わせからなる群より選ばれる物質とを含む粒子を投与する工程を含み、該粒子が肺系に送達される、パーキンソン病患者の治療方法。
- 粒子が塩をさらに含有する、請求項1記載の方法。
- 患者の気道に、約90重量パーセントを超えるレボドパ、非還元糖、またはリン脂質、および任意に塩から本質的になる粒子を投与する工程を含み、該粒子が肺系に送達され、約0.4g/cm3未満のタップ密度、約5マイクロメートルを超える容積メジアン幾何学的直径、および約1マイクロメートル〜約5マイクロメートルの空気力学的直径を有する、パーキンソン病患者の治療方法。
- 粒子が、約1マイクロメートル〜約3マイクロメートルの空気力学的直径を有する、請求項3記載の方法。
- 粒子が、約3マイクロメートル〜約5マイクロメートルの空気力学的直径を有する、請求項3記載の方法。
- 粒子が約0.3g/cm3未満のタップ密度を有する、請求項3記載の方法。
- 粒子が約0.2g/cm3未満のタップ密度を有する、請求項3記載の方法。
- 粒子が約0.1g/cm3未満のタップ密度を有する、請求項3記載の方法。
- 患者の気道に、約90重量パーセントを超えるレボドパおよび非還元糖を含む粒子を投与する工程を有し、該粒子が肺系に送達される、パーキンソン病患者の治療方法。
- 粒子が塩をさらに含有する、請求項9記載の方法。
- 非還元糖がトレハロースである、請求項9記載の方法。
- 患者の気道に、約90重量パーセントを超えるレボドパおよびリン脂質またはリン脂質の組み合わせを含む粒子を投与する工程を有し、該粒子が肺系に送達される、パーキンソン病患者の治療方法。
- 粒子が塩をさらに含有する、請求項12記載の方法。
- リン脂質がDPPCである、請求項12記載の方法。
- a)L−ドパおよびトレハロースを含む水溶液を形成する工程、
b)前記水溶液と有機溶液とを静かに混合して液体供給混合物を形成する工程、
c)前記液体供給混合物を噴霧乾燥する工程、ならびに
d)形成された噴霧乾燥粒子を回収する工程
を含み、改良点が噴霧乾燥前にNaClを該水溶液に添加することを含む、噴霧乾燥粒子の製造方法。 - 有機溶液がエタノールを含む、請求項15記載の方法。
- a)L−ドパ、トレハロースおよびNaClを含む水溶液を形成する工程、
b)前記水溶液と有機溶液とを静かに混合して液体供給混合物を形成する工程、ならびに
c)前記液体供給混合物を噴霧乾燥して、それにより噴霧乾燥粒子が形成される工程
を含む、噴霧乾燥粒子の製造方法。 - 有機溶液がエタノールを含む、請求項17記載の方法。
- a)L−ドパを含む水溶液を形成する工程、
b)DPPCを含む有機溶液を形成する工程、
c)前記水溶液と有機溶液とを静かに混合して液体供給混合物を形成する工程、
d)前記液体供給混合物を噴霧乾燥する工程、ならびに
e)形成された噴霧乾燥粒子を回収する工程
を含み、改良点が噴霧乾燥前にNaClを該水溶液に添加することを含む、噴霧乾燥粒子の製造方法。 - 有機溶液がエタノールを含む、請求項19記載の方法。
- a)L−ドパおよびNaClを含む水溶液を形成する工程、
b)DPPCを含む有機溶液を形成する工程、
c)前記水溶液と有機溶液とを静かに混合して液体供給混合物を形成する工程、ならびに
d)前記液体供給混合物を噴霧乾燥して、噴霧乾燥粒子を形成する工程
を含む、噴霧乾燥粒子の製造方法。 - 有機溶液がエタノールを含む、請求項21記載の方法。
- 約90重量%を超えるL−ドパおよび約10重量%未満のトレハロースを含む生体適合性粒子群。
- 約3重量%未満の塩化ナトリウムをさらに含む、請求項23記載の粒子群。
- 約90重量%を超えるL−ドパおよび約10重量%未満のDPPCを含む生体適合性粒子群。
- 約3重量%未満の塩化ナトリウムをさらに含む、請求項25記載の粒子群。
- L−ドパ、トレハロースおよびNaClから本質的になり、L−ドパが約90重量%を超える生体適合性粒子群。
- L−ドパ、DPPCおよびNaClから本質的になり、L−ドパが約90重量%を超える生体適合性粒子群。
- 約90重量%を超えるL−ドパおよび約10重量%未満のトレハロースまたはDPPCを含む粒子群を提供する工程、該粒子群を有する容器から分散と吸入とを同時に経て、粒子をヒトの被験体の気道に投与する工程を含む、肺系に有効量のL−ドパを送達する方法。
- 粒子が約3重量%未満の塩化ナトリウムをさらに含む、請求項29記載の方法。
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US36647102P | 2002-03-20 | 2002-03-20 | |
PCT/US2003/008659 WO2003079992A2 (en) | 2002-03-20 | 2003-03-19 | Pulmonary delivery for levodopa |
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EP (3) | EP1531798B1 (ja) |
JP (1) | JP4384503B2 (ja) |
AU (1) | AU2003218307B8 (ja) |
CA (1) | CA2478980C (ja) |
CY (1) | CY1118517T1 (ja) |
DK (2) | DK1531798T3 (ja) |
ES (3) | ES2609482T3 (ja) |
HU (1) | HUE031167T2 (ja) |
LT (1) | LT2630954T (ja) |
PT (3) | PT2630954T (ja) |
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