JP7467503B2 - 混合高分子ミセルを含有する医薬組成物 - Google Patents
混合高分子ミセルを含有する医薬組成物 Download PDFInfo
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- JP7467503B2 JP7467503B2 JP2021568699A JP2021568699A JP7467503B2 JP 7467503 B2 JP7467503 B2 JP 7467503B2 JP 2021568699 A JP2021568699 A JP 2021568699A JP 2021568699 A JP2021568699 A JP 2021568699A JP 7467503 B2 JP7467503 B2 JP 7467503B2
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Description
葉酸に結合されたリポポリマーをChoら,Journal of Nanomaterials,2015,16(1),論文番号36に報告されているプロトコルに従って調製した。
それぞれが異なる葉酸に結合されたカバジタキセルが負荷された混合高分子ミセル(「CBZ-mPM」)を含有する3種類の医薬組成物を、Choら,Journal of Nanomaterials,2015,16(1),論文番号36およびVakilら,Langmuir,2006,22,9723-9729に報告されているプロトコルに従って調製した。
D/P重量%=薬物の質量/総ポリマーの質量(mPEG-PCL+リポポリマー)×100%
DL(%)=ミセル中の薬物の質量/ミセル中の総ポリマーおよび薬物の質量×100%
EE(%)=濾過後の薬物の質量/濾過前の薬物の質量×100%
に従って計算した。
実施例2に記載されている5種類のCBZ-mPMのうちの3つ、すなわちDMB001、DFB001およびDFB002のインビトロ抗腫瘍活性を評価するために研究を行った。
細胞生存度(%)=(試料の570nmでのOD─ブランク試料のOD)/対照の570nmでのOD×100%
に従って計算した。
PEG5k-DSPE、葉酸-PEG5k-DSPE、またはPEG5k-DSPEおよび葉酸-PEG5k-DSPEの両方を含有する8種類の例示的なCBZ-mPMを、実施例2に記載されている手順に従って調製した。
実施例4に記載されている8種類のCBZ-mPMおよびCBZ-PMを6日間(144時間)の期間で25℃の水中に貯蔵した。粒径をレーザー粒径分析器(Beckman Delsa(商標)Nano S)で測定して貯蔵安定性を監視した。このようにして得られた安定性データが表3に示されている。
雌の胸腺欠損ヌードマウス(nu/nu、体重=20~25g)においてDFB014のインビボ抗腫瘍活性を調べた。このマウスの皮下に葉酸受容体を過剰発現するヒト表皮癌異種移植片細胞株、KB細胞(1匹の動物当たり2×107細胞)を埋め込んだ。埋め込み後に、腫瘍を約350mm3の体積に達するまで28日間増殖させ、その後に0日目に、PBSに懸濁させたジェブタナ(カバジタキセルの商品名)またはDFB014(当量の用量のカバジタキセル=10mg/kg)の単回用量をマウスの尾静脈に投与した。所定の時点でノギスを用いて腫瘍の長径および短径を測定した。次いで、式:(3/4)πa2b(式中、aおよびbはそれぞれ腫瘍の短径および長径の長さである)を用いて腫瘍体積を計算した。
TGI=(VTm-VT0)×100%/VT0
(式中、VTmは所定の時点における腫瘍体積であり、VT0は0日目すなわちジェブタナ/DFB014の投与当日における腫瘍体積である)
に従ってジェブタナおよびDFB014の腫瘍増殖阻害率%(「TGI」)を決定した。
蛍光イメージングによりCBZ-mPMのインビボでの腫瘍標的化を調べるために、近赤外染料すなわちCy5.5を、2種類の例示的なCBZ-mPMすなわちDMB025(葉酸を含有していない)およびDFB014(葉酸を含有している)の中に同時負荷して2種類のCy5.5含有CBZ-mPMすなわちCyDMB025およびCyDFB014を調製した。具体的には、出発物質へのCy5.5の添加により、実施例4に記載されているプロトコルに従って2種類のCy5.5含有CBZ-mPMを調製した。
実施例1に記載されている手順から改変された手順に従って、N-アセチル-ヒスチジンに結合されたリポポリマーを調製した。
実施例4に記載されている手順を改変することにより、DHB001、CBZ-mPMを含有するPEG5k-DSPEおよびNAcHis-PEG5k-DSPEを調製した。
本明細書に開示されている特徴の全てをあらゆる組み合わせで1つにまとめてもよい。本明細書に開示されている各特徴を同じ、同等もしくは同様の目的を果たす他の特徴で置き換えてもよい。従って明示的に別段の定めをした場合を除き、開示されている各特徴は一般的な一連の同等もしくは同様の特徴の例にすぎない。
Claims (9)
- 1~1000nmのサイズを有する混合高分子ミセルおよび前記ミセルに封入された薬物を含む医薬組成物であって、前記混合高分子ミセルは、両親媒性ブロックコポリマーおよびリガンドに結合された第1のリポポリマーを含有しており、ここでは前記両親媒性ブロックコポリマーはmPEG-PCLであり、前記第1のリポポリマーはPEG-DSPEであり、前記リガンドは葉酸またはN-アセチルヒスチジンであり、かつ前記薬物はカバジタキセルである、医薬組成物。
- 前記第1のリポポリマーは前記混合高分子ミセルの4~25重量%を構成している、請求項1に記載の医薬組成物。
- 1~1000nmのサイズを有する混合高分子ミセルおよび前記ミセルに封入された薬物を含む医薬組成物であって、前記混合高分子ミセルは、両親媒性ブロックコポリマー、リガンドに結合された第1のリポポリマーおよびリガンドに結合されていない第2のリポポリマーを含有しており、ここでは前記両親媒性ブロックコポリマーはmPEG-PCLであり、前記第1のリポポリマーおよび前記第2のリポポリマーはそれぞれPEG-DSPEであり、前記リガンドは葉酸またはN-アセチルヒスチジンであり、かつ前記薬物はカバジタキセルである、医薬組成物。
- 前記第1のリポポリマーおよび前記第2のリポポリマーは一緒に前記混合高分子ミセルの4~25重量%を構成している、請求項3に記載の医薬組成物。
- 1~1000nmのサイズを有する混合高分子ミセルおよび前記ミセルに封入された薬物を含む医薬組成物を調製する方法であって、
両親媒性ブロックコポリマー、リポポリマーおよび薬物を含む出発物質を提供する工程、
前記出発物質を溶媒中で混合する工程、
前記溶媒を除去して乾燥フィルムまたは乾燥ケーキを得る工程、
水を添加して前記乾燥フィルムまたは前記乾燥ケーキを可溶化して混合高分子ミセルを含有する溶液を形成する工程、および
前記溶液を濾過して医薬組成物を得る工程
を含み、
前記両親媒性ブロックコポリマーはmPEG-PCLであり、前記リポポリマーはPEG-DSPEでありおよびリガンドに結合されておらず、かつ前記薬物はカバジタキセルである、方法。 - 1~1000nmのサイズを有する混合高分子ミセルおよび前記ミセルに封入された薬物を含む医薬組成物であって、10~45%の薬物負荷を有する前記混合高分子ミセルは両親媒性ブロックコポリマーおよびリポポリマーを含有しており、ここでは前記両親媒性ブロックコポリマーはmPEG-PCLであり、前記リポポリマーはPEG-DSPEでありおよびリガンドに結合されておらず、かつ前記薬物はカバジタキセルである、医薬組成物。
- それを必要とする対象において癌を治療するのに使用するための、請求項1に記載の医薬組成物。
- それを必要とする対象において癌を治療するのに使用するための、請求項3に記載の医薬組成物。
- それを必要とする対象において癌を治療するのに使用するための、請求項6に記載の医薬組成物。
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