JP7167272B2 - 薬剤送達装置 - Google Patents
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Description
本出願は米国特許仮出願第62/196,558号および第62/196,568号(両方とも2015年7月24日出願)の優先権を主張し、その内容全体を参照により本明細書に組み込む。
真皮および表皮を含む皮膚の全体構造が図1に示されている。真皮は無数の組織タイプから成り、一般的に約500μm~約4,000μmの範囲の全厚を示す。リンパおよび毛細血管はしばしば図示するように一緒に見られるか、別々の実体として存在することができる。図示したように、血液および毛細リンパ管はしばしば、真皮乳頭層の一部内の真皮の上部内(例えば、表皮真皮または表皮基底膜の近く)に位置する。大きめの管は下部真皮網状層(例えば、示した血管)内に一般的に見られる。皮膚機能に重要なその他の組織タイプには、大きめの動脈、細動脈、汗腺管、皮脂腺、神経小体、結合組織および細胞外基質、平滑筋、ならびに毛包が含まれる。真皮網状層の下には皮下組織層があり、これは主に脂肪組織から成り、一般的にどのリンパ管または血管構造もない。
ニードルアレイをパッチ上に製作し、成体モルモットの皮膚内の薬剤送達深さの平均範囲を予測するために使用した。図5に示すように、メチレンブルー染料を約92μmの平均深さに投与し、約5μm~約200μmの深さ分布の範囲を示した(深さのガウス分布)。図6に示すように、皮膚の構造および深さは光干渉断層撮影技術を使用して予測しうる。ニードルアレイを適用した後の皮膚の構造は、皮膚の個別水平切片を調べることにより視覚化することができる。
ナノトポグラフィー表面を持つニードルアレイをパッチ上に製作し、Caco-2上皮細胞のインビトロ単層上で試験した。図7Aに示すように、ZO-1密着結合タンパク質は正常な染色パターンを示す。しかし、ナノトポグラフィー表面を持つニードルアレイをCaco-2細胞の近接部内に配置すると、破壊された染色パターンを見ることができる。このひだ状のパターンは、ナノトポグラフィーが位置した領域の接合部再構築を示す(図7B)。ナノトポグラフィーを持つニードルアレイを取り除くと染色パターンは正常に戻り、ZO-1などの密着結合タンパク質への空間的および時間的効果を示している(図7C)。
皮膚への投与によってタンパク質治療薬エタネルセプトをリンパ系に直接送達する能力を試験した。既述のように近赤外光を使用してインビボで可視化するために、エタネルセプトを蛍光標識した。Sevick-Muraca et al., J. Clin Invest., 124(3), 905-914 (2014)を参照のこと(これはその教示について、参照により本明細書に組み込まれる)。ラットの背部にニードルアレイを備える送達装置を配置することにより、エタネルセプトをラットの皮膚に投与した。図8および図9に示すように、エタネルセプトの皮膚への投与は、リンパ管構造による取り込みならびにその後の一次および二次リンパ節組織への分布をもたらした。
Claims (11)
- リンパ節炎の1つ以上の部位に1つ以上の生物活性薬剤を送達するべく構成された薬剤送達装置であって、1つ以上の生物活性薬剤が被験者に送達され、
前記薬剤送達装置は、2~50,000個の送達構造を有し、前記送達構造は、液体担体媒体に含められた前記1以上の薬剤と連通しており、前記1以上の薬剤を、リンパ管構造を持つ皮膚の1つ以上の部位に送達するように構成され、
前記薬剤送達装置は、表皮の1つ以上の層と、前記1つ以上の生物活性薬剤に対する前記表皮の1つ以上のバリア細胞の透過性の可逆的な増加を誘発する1つ以上の可逆的透過性促進剤とを接触させ、
前記透過性促進剤がナノ構造またはナノトポグラフィー表面を含み、
前記薬剤送達装置は、前記送達構造のそれぞれあたり0.01μl/時間~100μl/時間の制御投与流量、および前記被験者の前記皮膚と接触している1つ以上の前記薬剤送達装置の合計表面積に基づいて0.02μl/時間/cm2~50,000μl/時間/cm2の合計複合制御投与流量で、前記1つ以上の生物活性薬剤の2~50,000部分用量の合計液体投与量を投与できるように構成され、
前記1つ以上の生物活性薬剤の各部分用量が、前記表皮内の前記1つ以上の生物活性薬剤のその後の拡散または移動前に、前記表皮内の複数の独立深さに独立して投与され、
前記薬剤送達装置は、前記投与の後、前記1つ以上の生物活性薬剤が、前記表皮を通り前記表皮の基底層を通って、下にある生育可能な真皮の少なくとも一部分の中へとより深く移動または拡散して、1つ以上の毛細リンパ管叢によって前記1つ以上の生物活性薬剤の一部分の取り込みを達成し、同一の1つ以上の生物活性薬剤の静脈内、皮内、または皮下送達と比べて、リンパ管構造への前記1つ以上の生物活性薬剤のより大きな送達を達成し、
投与および取り込み後に、前記1つ以上の生物活性薬剤が、前記リンパ管構造を通り、1つ以上のリンパ節を含む1つ以上の二次リンパ組織へと循環し、それによりリンパ節炎の前記1つ以上の部位に前記1つ以上の生物活性薬剤を投与するように構成される、薬剤送達装置。 - 前記1つ以上の生物活性薬剤が、前記表皮内の前記1つ以上の生理薬剤のその後の拡散または移動前の前記1つ以上の生理薬剤を取り囲む表皮の0.7mm3~2,500mm3の組織容積に送達される、請求項1に記載の薬剤送達装置。
- 前記1つ以上の生物活性薬剤が0.1時間~96時間の間、被験者に連続的に投与される、請求項1に記載の薬剤送達装置。
- 1つ以上の生物活性薬剤の投与が、投与部位の下にある真皮の1mmHg~15mmHgの皮膚間質液圧を達成する、請求項1に記載の薬剤送達装置。
- 前記1つ以上のリンパ組織内の前記1つ以上の生物活性薬剤の相対濃度が、同一の1つ以上の生物活性薬剤の静脈内、皮内、または皮下送達よりも1.25倍~50倍高い、請求項1に記載の薬剤送達装置。
- 前記1つ以上の生物活性薬剤の血清吸収速度が、同一の1つ以上の生物活性薬剤の皮内送達および皮下送達と同等である、請求項1に記載の薬剤送達装置。
- リンパ節組織に対する全血液組織のグラムあたり局在化した1つ以上の生物活性薬剤の初期用量の比率が36時間後に5:1~15:1である、請求項1に記載の薬剤送達装置。
- リンパ節組織に対する皮膚組織のグラムあたり局在化した1つ以上の生物活性薬剤の初期用量の比率が36時間後に0.5:1~1:1である、請求項1に記載の薬剤送達装置。
- 前記生物活性薬剤が、少なくとも1つ以上の領域のリンパ節炎を含む自己免疫疾患を治療する、その進行を遅らせる、発症を遅延する、その予防、その寛解、または症状を減少するために有用である、請求項1に記載の薬剤送達装置。
- リンパ節炎の1つ以上の部位に1つ以上の生物活性薬剤を送達するべく構成された薬剤送達装置であって、1つ以上の生物活性薬剤が被験者に送達され、 前記薬剤送達装置は、2~50,000個の送達構造を有し、前記送達構造は、液体担体媒体に含められた前記1以上の薬剤と連通しており、前記1以上の薬剤を、リンパ管構造を持つ皮膚の1つ以上の部位に送達するように構成され、
前記薬剤送達装置は、表皮の1つ以上の層と、前記1つ以上の生物活性薬剤に対する前記表皮の1つ以上のバリア細胞の透過性の可逆的な増加を誘発する1つ以上の可逆的透過性促進剤とを接触させ、
前記透過性促進剤がナノ構造またはナノトポグラフィー表面を含み、
前記薬剤送達装置は、前記薬剤送達装置を通して制御された投与流量で、前記1つ以上の生物活性薬剤の2~50,000部分用量の合計液体投与量を投与できるように構成され、
前記1つ以上の生物活性薬剤の各部分用量が、前記表皮内の前記1つ以上の生物活性薬剤のその後の拡散または移動前に、前記表皮の最表面層を1μm~500μm超えている範囲の、前記表皮内の複数の独立深さに独立して投与され、
前記1つ以上の生物活性薬剤の合計液体投薬量が、1つ以上の生育可能な表皮層のみから成り、生育不能な表皮層は含まない前記表皮内の複数の深さに投与され、
前記薬剤送達装置は、前記投与の後、前記1つ以上の生物活性薬剤が、前記表皮を通り前記表皮の基底層を通って、下にある生育可能な真皮の少なくとも一部分の中へとより深く移動または拡散して、1つ以上の毛細リンパ管叢によって前記1つ以上の生物活性薬剤の一部分の取り込みを達成し、同一の1つ以上の生物活性薬剤の静脈内、皮内、または皮下送達と比べて、リンパ管構造への前記1つ以上の生物活性薬剤のより大きな送達を達成し、
投与および取り込み後に、前記1つ以上の生物活性薬剤が、前記リンパ管構造を通り、1つ以上のリンパ節を含む1つ以上の二次リンパ組織へと循環し、それによりリンパ節炎の前記1つ以上の部位に前記1つ以上の生物活性薬剤を投与するように構成される、薬剤送達装置。 - 前記生育可能な表皮内の前記複数の深さが、前記最も深い生育不能な表皮層を1μm~250μm超えるが、それでもまだ生育可能な表皮内にある深さである、請求項10に記載の薬剤送達装置。
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AU2016297832B2 (en) | 2020-07-16 |
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US20180193625A1 (en) | 2018-07-12 |
AU2016297832A1 (en) | 2018-02-15 |
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AU2020233748A1 (en) | 2020-10-08 |
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JP2021185160A (ja) | 2021-12-09 |
US10737082B2 (en) | 2020-08-11 |
CA2991459A1 (en) | 2017-02-02 |
EP3922238A1 (en) | 2021-12-15 |
KR20180035210A (ko) | 2018-04-05 |
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