JP2011502134A - 治療薬を含有する新規な温度感受性リポソーム - Google Patents
治療薬を含有する新規な温度感受性リポソーム Download PDFInfo
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- JP2011502134A JP2011502134A JP2010531403A JP2010531403A JP2011502134A JP 2011502134 A JP2011502134 A JP 2011502134A JP 2010531403 A JP2010531403 A JP 2010531403A JP 2010531403 A JP2010531403 A JP 2010531403A JP 2011502134 A JP2011502134 A JP 2011502134A
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- liposome
- temperature
- pharmaceutical composition
- liposomes
- anticancer agent
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Description
本発明の温度感受性リポソームは、1つ以上の活性薬剤を含むように処方してもよい。本明細書で用いる「活性薬剤」は、対象内の特定の部位に送達されるべき任意の化合物を含む。本発明の実施に際しては、任意の活性薬剤を用いてもよい。
本発明の温度感受性リポソームは、任意の適切な経路、例えば、静脈内投与、動脈内投与、筋肉内投与、腹腔内投与、皮下、皮内関節内、クモ膜下脳室内、鼻内噴霧、肺吸入、経口投与(oral dministration)および当業者に公知の他の適切な投与経路を用いて対象に投与することができる。本発明の方法を用いて処置可能な組織としては、鼻腔、肺、肝臓、腎臓、骨、軟組織、筋肉、副腎組織および胸部が挙げられるがこれらに限定されない。処置可能な組織には、癌組織または病変もしくは損傷組織と、所望であれば、健常組織の両方が含まれる。39.5℃よりも高い温度まで加熱可能な任意の組織または体液を本発明のリポソームを用いて処置してもよい。
温度感受性タキソテールリポソームの調製および特性評価
下記の原料を用いて本発明のリポソームを調製した:ジパルミトイルホスファチジルコリン(DPPC)、ジステアロイルホスファチジルグリセロール(DSPG)、モノステアロイルホスファチジルコリン(MSPC)、PEG化ジステアロイルホスファチジルエタノールアミン(DSPE−mPEG2000)、NaCl、KCl、Na2HPO4・12H2O、KH2PO4、ラクトース、CHCl3、メタノール、エタノールおよび蒸留水。
以下の成分を指定量だけ量り分けする。
上記リポソームの形態分析は電子顕微鏡法により行うことができる。リポソームをリンタングステン酸でネガティブ染色し、銅メッシュに移した。水分を蒸発させ、試料を電子顕微鏡で観察した。本発明の方法で調製したリポソームを電子顕微鏡で見ると均質であった。
本発明のリポソームを用いて得られたin vivo薬物分布と遊離ドセタキセルを用いて得られたin vivo薬物分布を比較した。
本発明のリポソームを用いて得られたin vivo薬物分布と非温度感受性ドセタキセル含有リポソームを用いて得られたin vivo薬物分布を比較した。
ルイス肺腫瘍を持つマウスにおいて、本発明のリポソームを用いたドセタキセル送達のin vivo有効性と遊離ドセタキセルのin vivo有効性を比較した。
ここで、Vsは生理食塩水群の腫瘍容積であり、Vxは処置群の腫瘍容積である。
カルボプラチンを含む温度感受性リポソームの調製
当業者に公知の任意の技術を用いてリポソームを調製してもよい。1つの適切な技術は以下の通りである。
カルボプラチン含有リポソームの物理的特性評価
薬物充填リポソームを遊離薬物から分離した後、そのリポソームは、下記表に見られるように、0.04の薬物/脂質比を有し、95nmの平均粒度を有する(図5および図6)。脂質濃度は106mg/mlである。
カルボプラチン含有リポソームの薬物放出プロファイルの特性評価
カルボプラチン薬物放出プロファイルを37℃および42℃で分析した。詳細な方法は以下の通りである。
下記表および図7は得られた結果を示す。
カルボプラチン含有リポソームの安定性の特性評価
異なる温度での保存時の薬物漏れを評価した。
Claims (37)
- 少なくとも1つのホスファチジルコリン、少なくとも1つのホスファチジルグリセロールおよび少なくとも1つのリゾ脂質を含む温度感受性リポソームであって、該リポソームは約39.0℃〜約45℃のゲル−液相転移温度を有する、温度感受性リポソーム。
- PEG化リン脂質をさらに含む、請求項1に記載の温度感受性リポソーム。
- 活性薬剤をさらに含む、請求項1に記載の温度感受性リポソーム。
- 前記ホスファチジルコリンはジパルミトイルホスファチジルコリン(DPPC)であり、前記ホスファチジルグリセロールはジステアロイルホスファチジルグリセロール(DSPG)であり、前記リゾ脂質はモノステアロイルホスファチジルコリン(MSPC)である、請求項1に記載の温度感受性リポソーム。
- PEG化リン脂質をさらに含む、請求項4に記載の温度感受性リポソーム。
- 前記PEG化脂質はPEG−2000修飾ジステアロイルホスファチジルエタノールアミン(DSPE−PEG2000)である、請求項5に記載の温度感受性リポソーム。
- DPPC:DSPG:MSPC:DSPE−PEG2000:活性薬剤を重量基準で60〜80:6〜12:6〜12:4〜15:1〜30の比率で含む、請求項1に記載の温度感受性リポソーム。
- 前記活性薬剤は抗癌剤である、請求項7に記載の温度感受性リポソーム。
- 前記抗癌剤は、アルキル化剤、代謝拮抗薬、紡錘体毒植物アルカロイド、細胞毒性抗腫瘍抗生物質、トポイソメラーゼ阻害剤、モノクローナル抗体もしくはその断片、光増感剤、キナーゼ阻害剤、抗腫瘍酵素および酵素の阻害剤、アポトーシス誘導物質、生物的反応修飾物質、抗ホルモン、レチノイド、ならびに白金含有化合物からなる群から選択される、請求項8に記載の温度感受性リポソーム。
- 前記抗癌剤はタキサンである、請求項9に記載の温度感受性リポソーム。
- 前記抗癌剤はドセタキセルである、請求項9に記載の温度感受性リポソーム。
- 前記抗癌剤は白金含有化合物である、請求項9に記載の温度感受性リポソーム。
- 前記抗癌剤はカルボプラチンまたはシスプラチンである、請求項9に記載の温度感受性リポソーム。
- 活性薬剤を含む温度感受性リポソームを含む医薬組成物であって、該リポソームは、少なくとも1つのホスファチジルコリン、少なくとも1つのホスファチジルグリセロール、少なくとも1つのリゾ脂質を含み、約39.0℃〜約45℃のゲル−液相転移温度を有する、医薬組成物。
- 前記リポソームはPEG化リン脂質をさらに含む、請求項14に記載の医薬組成物。
- 前記ホスファチジルコリンはジパルミトイルホスファチジルコリン(DPPC)であり、前記ホスファチジルグリセロールはジステアロイルホスファチジルグリセロール(DSPG)であり、前記リゾ脂質はモノステアロイルホスファチジルコリン(MSPC)である、請求項14に記載の医薬組成物。
- 前記リポソームはPEG化リン脂質をさらに含む、請求項16に記載の医薬組成物。
- 前記PEG化脂質はPEG−2000修飾ジステアロイルホスファチジルエタノールアミン(DSPE−PEG2000)である、請求項17に記載の医薬組成物。
- 前記リポソームは、DPPC:DSPG:MSPC:DSPE−PEG2000:活性薬剤を重量基準で60〜80:6〜12:6〜12:4〜15:1〜30の比率で含む、請求項14に記載の医薬組成物。
- 前記活性薬剤は抗癌剤である、請求項19に記載の医薬組成物。
- 前記抗癌剤は、アルキル化剤、代謝拮抗薬、紡錘体毒植物アルカロイド、細胞毒性抗腫瘍抗生物質、トポイソメラーゼ阻害剤、モノクローナル抗体もしくはその断片、光増感剤、キナーゼ阻害剤、抗腫瘍酵素および酵素の阻害剤、アポトーシス誘導物質、生物的反応修飾物質、抗ホルモン、レチノイド、ならびに白金含有化合物からなる群から選択される、請求項20に記載の医薬組成物。
- 前記抗癌剤はタキサンである、請求項20に記載の医薬組成物。
- 前記抗癌剤はドセタキセルである、請求項20に記載の医薬組成物。
- 前記抗癌剤は白金含有化合物である、請求項20に記載の医薬組成物。
- 前記抗癌剤はカルボプラチンまたはシスプラチンである、請求項20に記載の医薬組成物。
- 処置を必要とする対象の疾患を処置する方法であって、
活性薬剤を含む感温性リポソームを含む治療有効量の医薬組成物を該対象に投与する工程であって、該リポソームは、少なくとも1つのホスファチジルコリン、少なくとも1つのホスファチジルグリセロール、少なくとも1つのリゾ脂質を含み、約39.0℃〜約45℃のゲル−液相転移温度を有する、工程と、
該疾患の全てまたは一部を含む該対象の領域を加熱する工程と、
を包含する、方法。 - 前記リポソームはPEG化リン脂質をさらに含む、請求項26に記載の方法。
- 前記ホスファチジルコリンはジパルミトイルホスファチジルコリン(DPPC)であり、前記ホスファチジルグリセロールはジステアロイルホスファチジルグリセロール(DSPG)であり、前記リゾ脂質はモノステアロイルホスファチジルコリン(MSPC)である、請求項26に記載の方法。
- 前記リポソームはPEG化リン脂質をさらに含む、請求項28に記載の方法。
- 前記PEG化脂質はPEG−2000修飾ジステアロイルホスファチジルエタノールアミン(DSPE−PEG2000)である、請求項29に記載の方法。
- 前記リポソームは、DPPC:DSPG:MSPC:DSPE−PEG2000:活性薬剤を重量基準で60〜80:6〜12:6〜12:4〜15:1〜30の比率で含む、請求項26に記載の方法。
- 前記疾患は癌であり、前記活性薬剤は抗癌剤である、請求項31に記載の方法。
- 前記抗癌剤は、アルキル化剤、代謝拮抗薬、紡錘体毒植物アルカロイド、細胞毒性抗腫瘍抗生物質、トポイソメラーゼ阻害剤、モノクローナル抗体もしくはその断片、光増感剤、キナーゼ阻害剤、抗腫瘍酵素および酵素の阻害剤、アポトーシス誘導物質、生物的反応修飾物質、抗ホルモン、レチノイド、ならびに白金含有化合物からなる群から選択される、請求項32に記載の方法。
- 前記抗癌剤はタキサンである、請求項32に記載の方法。
- 前記抗癌剤はドセタキセルである、請求項32に記載の方法。
- 前記抗癌剤は白金含有化合物である、請求項32に記載の方法。
- 前記抗癌剤はカルボプラチンまたはシスプラチンである、請求項32に記載の方法。
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JP2014503582A (ja) * | 2011-01-28 | 2014-02-13 | コーニンクレッカ フィリップス エヌ ヴェ | 親水性プロドラッグの局所放出用担体 |
WO2013172358A1 (ja) * | 2012-05-14 | 2013-11-21 | 公立大学法人大阪府立大学 | 機能性化合物及びその化合物を含有する分子集合体、並びにそれらを含有する組成物及びキット並びにそれらの使用 |
Also Published As
Publication number | Publication date |
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KR20100087030A (ko) | 2010-08-02 |
EP2217209A4 (en) | 2013-09-25 |
MX2010004957A (es) | 2010-08-02 |
RU2010123009A (ru) | 2011-12-20 |
EP2217209B1 (en) | 2018-06-06 |
JP5570994B2 (ja) | 2014-08-13 |
WO2009059449A1 (en) | 2009-05-14 |
US20110200665A1 (en) | 2011-08-18 |
TW200930380A (en) | 2009-07-16 |
CN101883557A (zh) | 2010-11-10 |
MY151268A (en) | 2014-04-30 |
ES2689259T3 (es) | 2018-11-12 |
CN101883557B (zh) | 2013-05-29 |
HK1146906A1 (en) | 2011-07-22 |
WO2009062398A1 (en) | 2009-05-22 |
CA2704258C (en) | 2016-11-22 |
AU2008323514B2 (en) | 2014-06-12 |
KR101652126B1 (ko) | 2016-08-29 |
TWI437995B (zh) | 2014-05-21 |
AU2008323514A2 (en) | 2012-05-17 |
CA2704258A1 (en) | 2009-05-22 |
US8642074B2 (en) | 2014-02-04 |
EP2217209A1 (en) | 2010-08-18 |
BRPI0820505A2 (pt) | 2015-06-16 |
RU2497499C2 (ru) | 2013-11-10 |
AU2008323514A1 (en) | 2009-05-22 |
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