JP5639338B2 - リポソームの製造システムおよび製造方法 - Google Patents
リポソームの製造システムおよび製造方法 Download PDFInfo
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- JP5639338B2 JP5639338B2 JP2008523088A JP2008523088A JP5639338B2 JP 5639338 B2 JP5639338 B2 JP 5639338B2 JP 2008523088 A JP2008523088 A JP 2008523088A JP 2008523088 A JP2008523088 A JP 2008523088A JP 5639338 B2 JP5639338 B2 JP 5639338B2
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Description
本願は、その全体が参照により本明細書に組み入れられる、2005年7月27日に出願された米国出願番号第60/703,380号、表題「SYSTEMS AND METHODS FOR MANUFACTURING LIPOSOMES」の恩典を主張する非仮出願である。
活性物質を細胞に投与する多くシステム、例えばリポソーム、ナノ粒子、ポリマー粒子、免疫複合体およびリガンド複合体、ならびにシクロデキストリンが、すでに公知である(Drug Transport in antimicrobial and anticancer chemotherapy, G. Papadakou Ed., CRC Press, 1995を参照のこと)。リポソームは典型的には、超音波処理法、界面活性剤透析法、エタノール注入または希釈法、フレンチプレス押出し法、エーテル注入法、および逆相蒸発法により
研究室内で調製される。複数の二重層を有するリポソームは、多重層脂質小胞(multilamellar lipid vesicle)(MLV)として公知である。その層間に捕捉された流体は各々の膜の分解によってのみ放出されるので、MLVは徐放薬の候補である。単一の二重層を有するリポソームは単層脂質小胞(unilamellar lipid vesicle)(UV)として公知である。UVは、小型(SUV)または大型(LUV)のものが製造され得る。
本発明は、任意で治療剤を含有する脂質小胞の製造プロセスおよび製造装置を提供する。治療剤には、例えば、タンパク質、核酸、アンチセンス核酸、薬物等が含まれ得る。本発明は、核酸または低分子薬を被包して含む脂質小胞を形成するのに使用され得る。一つの局面において、脂質小胞は低圧下で迅速に調製され、かつこのアプローチは十分拡大可能である。特定の好ましい態様において、このプロセスはスタティックミキサーまたは専用の押出し機器を使用しない。
I.定義
「核酸」という用語は、少なくとも二つのヌクレオチドを含むポリマーを意味する。「ヌクレオチド」は、糖デオキシリボース(DNA)またはリボース(RNA)、塩基、およびリン酸基を含む。ヌクレオチドはリン酸基を通じて連結される(ただし合成核酸は、リン酸基以外のヌクレオチドリンカーを用いて調製され得る)。「塩基」にはプリンおよびピリミジンが含まれ、さらにプリンおよびピリミジンには、天然化合物であるアデニン、チミジン、グアニン、シトシン、ウラシル、イノシン、ならびにプリンおよびピリミジンの天然アナログおよび合成性誘導体が含まれ、プリンおよびピリミジンの合成性誘導体には、例えばアミン、アルコール、チオール、カルボキシレート、およびハロゲン化アルキルであるがこれらに限定されない新しい反応基を加えた修飾体が含まれるがこれらに限定されない。
が含まれる。
本発明は、脂質小胞の製造プロセスおよび製造装置を提供する。このプロセスは、陽イオン性脂質、陰イオン性脂質、中性脂質、ポリエチレングリコール(PEG)脂質、親水性ポリマー脂質、膜融合性脂質、およびステロールを含むがこれらに限定されない幅広い脂質成分を含む脂質小胞を製造するのに使用され得る。疎水性の活性物質は、脂質を含む有機溶媒(例えばエタノール)に混入され、核酸および親水性の活性物質は水性成分に加えられ得る。特定の局面において、本発明のプロセスは、脂質単層が油ベースのコアを取り囲むマイクロエマルジョンを調製するのに使用され得る。特定の局面において、このプロセスおよび装置は、脂質小胞またはリポソームの調製に使用され得、治療剤はリポソームの形成と同時にリポソーム内に被包される。
図1は、本発明の方法の代表的なフローチャート100の一例である。このフローチャートは例示にすぎず、特許請求の範囲を限定すべきではない。当業者は、他のバリエーション、改良物、および代用物を認識するであろう。
一つの態様において、本発明のプロセスに従い製造されるリポソーム小胞は、安定な核酸脂質粒子(すなわちSNALP)処方物を含む。当業者は、以下の解説が例示目的にすぎないことを理解するであろう。本発明のプロセスは、幅広い脂質小胞のタイプおよびサイズに適用できる。これらの脂質小胞には、小型(SUV)または大型(LUV)のものが製造され得る単層脂質小胞として公知の単層脂質小胞、および多重層脂質小胞(MLV)が含まれるがこれらに限定されない。さらなる小胞には、ミセル、脂質-核酸粒子、ビロソーム等が含まれる。当業者は、本発明のプロセスおよび装置に適するその他の脂質小胞を認識しているであろう。
溶液、例えば脂質溶液120および治療剤(例えば核酸)水溶液115を調製した後、これらは、例えば蠕動ポンプミキサーまたはパルスレスギアポンプを用いて混合130される。一つの局面において、これらの溶液は実質的に等しい流速で混合環境にくみ出されるが、非同一の流速も使用され得る。特定の局面において、混合環境は「T」字型コネクタまたは混合チャンバを含む。この例において、流路、従って流体の流れは、互いとおよそ180°反対方向の流れとして「T」字コネクタの狭い通路(aperture)で出会う。浅い相対導入角、例えば27°〜90°および90°〜180°の相対導入角を有する他の混合チャンバまたはコネクタも使用され得る。溶液の流れが混合環境で出会い混合されると、脂質小胞が実質的に即時に形成される。脂質小胞は、脂質を溶解して含む有機溶液と水溶液(例えば緩衝液)が同時かつ連続的に混合される場合に形成される。水溶液を有機脂質溶液と混合することにより、有機脂質溶液が連続的、逐次的な段階的希釈を受け、実質的に即時にリポソーム溶液(リポソームの懸濁物)を生成するのは有利なことであり、驚くべきことである。ポンプ機構は、高アルカノール環境下で脂質小胞を形成する混合環境に脂質溶液と水溶液が等しい流速または異なる流速で供給されるよう設定され得る。
図1に話を戻すが、小胞形成工程130後の治療剤(例えば核酸)の被包の程度は、遊離の核酸を除去する前に脂質小胞懸濁物(リポソーム溶液)を即時に希釈140することにより向上し、粒子サイズは維持され、小型化さえする。例えば、希釈工程140の前の治療剤の捕捉が約50〜60%の場合、希釈工程140後にそれを約80〜90%まで上昇させることができる。工程140において、リポソーム処方物は、水溶液、例えば緩衝液と混合する(例えば、20mMクエン酸緩衝液、300mM NaCl、pH6.0と1:1に)ことにより約10%〜約40%、好ましくは約20%アルカノールまで希釈される。次いで希釈されたサンプルは、必要に応じて室温でインキュベートされる。
即時希釈140の後、治療剤(例えば核酸)の約70〜80%またはそれ以上が脂質小胞(例えばSNALP)に捕捉され、遊離の治療剤は処方物から除去150され得る。特定の局面において、陰イオン交換クロマトグラフィが使用される。陰イオン交換樹脂の使用は、高い動的な核酸除去効果を示し、単独使用が可能であり、前もって滅菌および検証され得、十分に拡大可能である点が有利である。さらに、この方法は遊離の治療剤(例えば総プラスミドのおよそ25%の核酸)を除去する。クロマトグラフィ後のサンプル量は変化せず、治療剤(例えば核酸)および脂質の濃度は、それぞれ約0.04〜0.05および0.7mg/mLである。この時点で、治療剤の被包についてサンプルをアッセイしてもよい。
特定の例において、リポソーム溶液は、必要に応じて、例えば限外濾過160(例えばタンジェンシャルフロー型透析)を用いて約5〜50倍、好ましくは10〜20倍濃縮される。一つの態様において、サンプルは限外濾過システムの供給レザバーに移され、緩衝液が除去される。緩衝液は、様々なプロセスを用いて、例えば、限外濾過によって除去できる。一つの局面において、緩衝液は、例えば約0.5mm〜約1.0mmの内径および30,000の名目分子量カットオフ(NMWC)を有するポリスルホン中空糸を積み込んだカートリッジを用いて除去される。約1,000 MWCO〜約750,000 MWCOを有する中空糸もまた使用され得る。リポソームは中空糸内に保持され再循環されるが、溶媒および低分子は中空糸の孔を通過することによって処方物から除去される。この手順における濾液は透過溶液として公知である。濃縮工程の完遂時、治療剤(例えば核酸)および脂質の濃度は、それぞれ約2および60mg/mLに増加し得る。一つの態様において、アルカノールの濃度は変化しないが、アルカノール:脂質の比が約50倍減少する。
一つの態様において、濃縮された処方物は、約5〜20倍量、好ましくは10倍量の水溶液(例えば緩衝液)(例えばクエン酸緩衝液、pH4.0(25mMクエン酸、100mM NaCl))に対して透析濾過され、アルカノールが除去170される。中性緩衝液または糖系緩衝液もまた使用され得る。工程170完遂時のアルカノール濃度は約1%未満である。脂質および治療剤(例えば核酸)の濃度は変化せず、治療剤の捕捉レベルも一定に保たれる。
アルカノールが除去された後、次いで水溶液(例えば緩衝液)が別の緩衝液に対する(例えば10倍量の10mM Hepesまたはリン酸含有を含有する生理食塩水150mM NaCl、pH7.4に対する)透析濾過により置換180される。様々な緩衝液、例えば中性緩衝液、糖系緩衝液等、のいずれかが使用され得る。典型的には、治療剤(例えば核酸)に対する脂質の濃度比は変化せず維持され、核酸の捕捉レベルはほぼ一定である。特定の例において、サンプルの収量は濃縮サンプルの約10%の量の緩衝液を含むカートリッジでリンスすることによって改善され得る。特定の局面において、このリンス液はその後濃縮サンプルに追加される。
特定の好ましい態様において、脂質濃度が約12〜120mg/mLのサンプルの滅菌濾過190が必要に応じて行われ得る。特定の局面において、濾過は、カプセルフィルターおよび加熱ジャケットを備える加圧分注容器を用いて約40psi未満の圧力下で行われる。サンプルの加熱は、濾過の難易度を若干改善し得る。
滅菌充填工程195は、従来的なリポソーム処方と同様のプロセスを用いて行われる。本発明のプロセスにより、当初の治療剤(例えば核酸)の約50〜60%が最終産物に含まれることになる。特定の局面において、最終産物の脂質に対する治療剤の比はおよそ0.01〜0.2である。
本発明の脂質系薬物処方物および組成物は、治療剤または生物活性薬剤の全身送達または局所送達に有用であり、かつ診断アッセイにも有用である。以下の議論は主としてリポソームを参照しているが、当業者はこれと同じ議論が本発明の他の薬物送達系にも十分適用できることを容易に理解するであろう。
一つの態様において、本発明は、本発明のプロセスを実行するためのシステムおよび装置を提供する。図3aおよび3bは、本発明の二つの態様に従う、それぞれ装置300および装置302の例を示す。これらの概略図は例示にすぎず、特許請求の範囲を限定すべきではない。当業者は、他のバリエーション、改良物、代用物を認識するであろう。
実施例1 - 先行技術の方法と直接希釈プロセスの比較
SNALPは、2mol% PEG-C-DMA、30% DlinDMA、20mol% DSPC、および48mol% Chol''で構成される。
→ 核酸:非修飾siRNA(0.9% NaClで再構成)(0.225mg/ml siRNA)
→ 混合量:10mLの核酸 + 10mLの脂質-エタノール溶液(5mM脂質)
→ 1.6mm T字コネクタ、3.2mmチューブ、チャンネル毎に40cmチューブ長
→ 流速:200mL/分
1.核酸と脂質を混合し、次いでインキュベーション猶予後にポンプを用いてSNALPを希釈する(先行技術の方法)。
2. 核酸と脂質を混合し、次いでピペットを用いて緩衝液を追加することでSNALPを希釈する。
3.希釈緩衝液を含むボトルで直接的に核酸と脂質を混合する(撹拌を除いた図3a)。
4.撹拌された希釈緩衝液中で直接的に核酸と脂質を混合する(図3a)。
直接希釈(図3a)対インライン希釈(図3b)
*流速の値は希釈前の初期小胞形成時の速度の値であり、希釈緩衝液はインライン希釈法については得られるSNALPサンプルにおいて20% EtOHを達成するよう600mL/分で送達される。
1.SNALPは、ポンプ流速を上げ、siRNA溶液、脂質溶液、および希釈緩衝液に対して修正を加えた場合に高い脂質およびsiRNAの初期濃度(4倍)で調製できる。これらのSNALPは良い被包効率および粒子サイズを有する。
2.インライン希釈アプローチ(SNALP3 - 図3b)を用いることで、これらのSNALP粒子の粒子サイズはさらに制御でき、脂質およびsiRNAの初期濃度の4分の1で調製されたSNALP2(図3a)と同様のサイズの粒子を生成する。
本発明のシステムおよび方法を用いて製造され得る脂質粒子のさらなる特徴、利点、および例は、本願と同時の2005年7月27日に出願した米国仮特許出願番号[60/](代理人管理番号020801-002810US)、表題「siRNA Silencing of Apoliprotein B」において見出すことができ、その内容は参照により本明細書に組み入れられる。本明細書中で議論した全ての特許、特許出願、およびその他の参考文献は、参照として本明細書に組み入れられる。
Claims (31)
- 治療用製品を被包する脂質小胞の製造方法であって、
第一レザバーに水溶液を供給する工程;
第二レザバーに有機脂質溶液を供給する工程であって、水溶液および有機脂質溶液の一方が治療用製品を含む、工程;
第一混合区画で水溶液と有機脂質溶液を混合して脂質小胞溶液を生成する工程であって、有機脂質溶液が、治療用製品を被包する脂質小胞を実質的に即時に生成するよう水溶液と混合され、ここで、混合は、実質的に等しい流速で前記水溶液および前記有機脂質溶液を前記第一混合区画に導入することを含み、該第一混合区画が第一T字コネクタを含み、該水溶液および該有機脂質溶液が実質的に互いと180°反対方向の流れとして該第一T字コネクタに導入される、工程;ならびに
脂質小胞溶液を緩衝溶液と混合して脂質小胞希釈溶液を生成する工程であって、該脂質小胞溶液と該緩衝溶液との混合は、第二混合区画で混合することを含み、前記第一混合区画内で形成された脂質小胞溶液は即時かつ直接的に該第二混合区画に導入され、該第二混合区画が第二T字コネクタを含み、該脂質小胞溶液および該緩衝溶液が実質的に互いと27°〜180°の角度で該第二T字コネクタに導入される、工程
を含む方法。 - 脂質小胞溶液が20% v/v〜55% v/vの有機溶媒濃度を有する、請求項1記載の方法。
- 脂質小胞希釈溶液が25% v/v未満の有機溶媒濃度を有する、請求項2記載の方法。
- 脂質小胞の直径が100nm未満である、請求項1記載の方法。
- 治療用製品が、タンパク質、プラスミド、アプタマー、核酸、アンチセンス核酸、リボザイム、tRNA、snRNA、siRNA、shRNA、ncRNA、凝縮型DNA、および抗原からなる群より選択される、請求項1記載の方法。
- 治療用製品を被包する脂質小胞の製造装置であって、
水溶液を保持する第一レザバー;
有機脂質溶液を保持し、水溶液および有機脂質溶液の一方が治療用製品を含む、第二レザバー;
水溶液と有機脂質溶液を実質的に等しい流速で第一混合区画にくみ上げるように構成された第一ポンプ機構であって、有機脂質溶液が第一混合区画において治療用製品を被包する脂質小胞の溶液を実質的に即時に生成するよう水溶液と混合され、ここで、該第一混合区画が第一T字コネクタを含み、該水溶液および該有機脂質溶液が実質的に互いと180°反対方向の流れとして該第一T字コネクタに導入される、第一ポンプ機構;
緩衝溶液を保持する緩衝レザバー;ならびに
緩衝溶液を制御された流速で第二混合区画にくみ上げるように構成された第二ポンプ機構であって、脂質小胞溶液が第一混合区画において形成された後、即時かつ直接的に第二混合区画に導入され、ここで該第二混合区画が第二T字コネクタを含み、該脂質小胞溶液および該緩衝溶液が互いと27°〜180°の角度で該第二T字コネクタに導入され、それにより第二混合区画において脂質小胞希釈溶液が形成される、第二ポンプ機構
を含む装置。 - 緩衝溶液の流速が、第二T字コネクタに流入する脂質小胞溶液の流速と実質的に等しいまたはそれよりも速くなるように制御される、請求項6記載の装置。
- 脂質小胞溶液が20% v/v〜55% v/vの有機溶媒濃度を有する、請求項6記載の装置。
- 脂質小胞希釈溶液が25% v/v未満の有機溶媒濃度を有する、請求項8記載の装置。
- 脂質小胞の直径が100nm未満である、請求項6記載の装置。
- 治療用製品が、タンパク質、プラスミド、アプタマー、核酸、アンチセンス核酸、リボザイム、tRNA、snRNA、siRNA、shRNA、ncRNA、凝縮型DNA、および抗原からなる群より選択される、請求項6記載の装置。
- 前記脂質小胞が安定な核酸−脂質粒子(SNALP)である、請求項1記載の方法。
- 前記脂質粒子がリポソームである、請求項1記載の方法。
- 前記有機脂質溶液中に存在する脂質が有機溶媒中に溶解する、請求項1記載の方法。
- 前記有機溶媒が低級アルカノールである、請求項14記載の方法。
- 前記低級アルカノールが、メタノール、エタノール、プロパノール、ブタノール、ペンタノール、これらの異性体、およびこれらの混合物からなる群から選択される、請求項15記載の方法。
- 前記低級アルカノールが、100% v/vのエタノールを含む、請求項15記載の方法。
- 前記有機脂質溶液中に存在する脂質が、リン脂質、コレステロール、PEG−脂質、および陽イオン性脂質を含む、請求項1記載の方法。
- 前記水溶液が前記治療用製品を含む、請求項1記載の方法。
- 前記水溶液が4〜6のpHを有する、請求項19記載の方法。
- 前記脂質小胞希釈溶液が、17% v/v〜25% v/vの有機溶媒濃度を有する、請求項2記載の方法。
- 前記脂質小胞が安定な核酸−脂質粒子(SNALP)である、請求項6記載の装置。
- 前記脂質粒子がリポソームである、請求項6記載の装置。
- 前記有機脂質溶液中に存在する脂質が有機溶媒中に溶解する、請求項6記載の装置。
- 前記有機溶媒が低級アルカノールである、請求項24記載の装置。
- 前記低級アルカノールが、メタノール、エタノール、プロパノール、ブタノール、ペンタノール、これらの異性体、およびこれらの混合物からなる群から選択される、請求項25記載の装置。
- 前記低級アルカノールが、100% v/vのエタノールを含む、請求項25記載の装置。
- 前記有機脂質溶液中に存在する脂質が、リン脂質、コレステロール、PEG−脂質、および陽イオン性脂質を含む、請求項6記載の装置。
- 前記水溶液が前記治療用製品を含む、請求項6記載の装置。
- 前記水溶液が4〜6のpHを有する、請求項29記載の装置。
- 前記脂質小胞希釈溶液が、17% v/v〜25% v/vの有機溶媒濃度を有する、請求項6記載の装置。
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