JP2019533073A - ポリマー粒子 - Google Patents
ポリマー粒子 Download PDFInfo
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- JP2019533073A JP2019533073A JP2019531190A JP2019531190A JP2019533073A JP 2019533073 A JP2019533073 A JP 2019533073A JP 2019531190 A JP2019531190 A JP 2019531190A JP 2019531190 A JP2019531190 A JP 2019531190A JP 2019533073 A JP2019533073 A JP 2019533073A
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- 125000000524 functional group Chemical group 0.000 claims description 31
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Abstract
Description
本出願は、2016年9月28日に出願された米国仮特許出願第62/401,091号明細書および2016年12月1日に出願された米国仮特許出願第62/428,990号明細書の利益を主張し、その全開示は参照により本明細書に組み込まれる。
腫瘍の塞栓形成または動静脈奇形などの、体内の血管部位および体腔の閉塞のための生分解性ポリマー粒子が記載される。
(実施例1)
生分解性架橋剤
生分解性架橋剤
生分解性架橋剤
生分解性架橋剤
生分解性架橋剤
生分解性架橋剤
生分解性架橋剤
粒子の調製
鉱油(300mL)を、オーバーヘッド撹拌素子および70℃に維持された加熱素子を備えた密閉ジャケット付き反応容器に添加した。混合しながら容器をアルゴンで少なくとも4時間スパージした。1.5gのジメチルアクリルアミド、1.5gのグリセロールモノメタクリレート、4.6gの3−スルホプロピルアクリレート、0.35gのアゾビスイソブチロニトリル、および実施例1〜7で調製した5.5gの架橋剤を25.0gのN,N−ジメチルホルムアミドに溶解することによってプレポリマー溶液を調製した。溶解したら、溶液をアルゴンで5分間スパージした。アゾビスイソブチロニトリル(0.40g)を反応容器に添加し、そしてオーバーヘッド撹拌を300rpmに上げた。約10分後、一定分量のSPAN(登録商標)80(0.8mL)を鉱油に加えて混合した。プレポリマー溶液を反応容器に添加し、得られた懸濁液を1時間重合させた後、加熱を止めた。得られた溶液を反応容器中で一晩混合した。
粒子の精製
重合が完了した後、一定分量のヘキサンを反応容器に加え、ポリマー粒子を洗浄して、残った鉱油を除去した。粒子を溶液から分離し、一定分量のN,N−ジメチルホルムアミドで洗浄した。ヘキサンおよびN,N−ジメチルホルムアミドについて、新しい部分の溶液による洗浄を繰り返した。得られた混合物をリン酸緩衝食塩水(PBS)で3回洗浄した。
粒子の分解
異なるモノマー、架橋剤および試薬濃度で調製された粒子のサンプルをPBSに入れ、37℃で保存して分解時間を測定した。視覚分析は、粒子の色および透明度、粒子の輪郭を見る能力、および見える粒子の数を含んだ。サンプルの評価スケールは、(5)実験開始時から粒子数、輪郭、または量に変化がない、(3)多数の粒子が見えるが粒子の輪郭がかすんでいる、(1)粒子がほとんど見えない、(0)サンプル中に粒子が観察されない、を含んだ。異なる架橋剤の比較の結果を図1に示す。結果は、分解速度が使用される架橋剤の構造に依存され得ることを示す。
粒子からの医薬品のin vitro溶出
in vitro溶出試験のために、薬物を直径約400±100ミクロンのミクロスフェアの1mLのサンプルに担持した。一定分量のミクロスフェアに、水中の37.5mgのドキソルビシンまたはクエン酸緩衝液中の50mgのイリノテカンを担持した。サンプルを18時間インキュベートした。Sotax USP 4溶解装置でサンプルから薬物を溶出した。サンプルを漸増時間間隔で採取し、そして高速液体クロマトグラフィーにより分析した。ピーク面積を記録した(図4)。溶出した薬物のパーセントおよび濃度を各時間間隔について計算した。37.5mgのドキソルビシンを担持した1mLのミクロスフェアサンプルは、初日に24.5mg(65%)を溶出し、そして、50mgのイリノテカンを担持したサンプルは、初日に45mg(95%)超を溶出した。
粒子からの医薬品のin vivo溶出
塞栓形成前および塞栓形成後20、40、60、120および180分に医薬品の全身濃度を測定するために血液サンプルを採取した。遠心分離により血漿を調製し、分析するまでサンプルを−80℃で凍結した。ABSciex 4000 Q Trap LC/MS/MSシステムと組み合わせたAgilent 1260 Infinity HPLCシステムを使用して、液体クロマトグラフィー−タンデム質量分析(LC/MS/MS)によって定量を行った。クロマトグラフィー分離は、25℃でAgilent Poroshell 120 C18カラム(4.6mm×50mm、2.7μm)、ならびにA:アセトニトリル中0.1%ギ酸およびB:0.1%のギ酸水溶液からなる移動相を使用して行った。血漿サンプルを、50ppbの内部標準を含有する3倍過剰(v/v)のアセトニトリルで沈殿させた。ボルテックスし、4℃、13,000rpmで10分間遠心した後、各サンプルの上清を0.1%のギ酸水溶液で希釈した。希釈したサンプルを20μL注入した。較正曲線は、各薬剤の分析範囲にわたってブランク血漿をスパイクすることによって作成した。血漿中経時的な各薬剤の全身濃度を図5および6に示す。
粒子の調製
鉱油(500mL)を、オーバーヘッド撹拌素子および74℃に維持された加熱素子を備えた密閉ジャケット付き反応容器に添加した。混合しながら容器をアルゴンで少なくとも4時間スパージした。0.5gのジメチルアクリルアミド、2.75gのグリセロールモノメタクリレート、4.9gの3−スルホプロピルアクリレート、0.35gのアゾビスイソブチロニトリル、および実施例1〜7で調製した5.25gの架橋剤を25.0gのジメチルスルホキシドに溶解することによってプレポリマー溶液を調製した。溶解したら、溶液をアルゴンで5分間スパージした。所望ならば、一定分量のTriton(登録商標)X−100(0.2mL)を製剤に添加して混合し得る。アゾビスイソブチロニトリル(0.50g)を反応容器に添加し、そしてオーバーヘッド撹拌を325rpmに高めた。約2分後、一定分量のSPAN(登録商標)80(2.5mL)を鉱油に加えて混合した。プレポリマー溶液を反応容器に添加し、得られた懸濁液を1時間重合させた後、加熱を止めた。得られた溶液を反応容器中で一晩混合した。
粒子の洗浄
重合が完了した後、一定分量のヘキサンを反応容器に加え、ポリマー粒子を洗浄して、残った鉱油を除去した。粒子を溶液から分離し、新しい部分の溶液で洗浄することを繰り返した。粒子をもう一度溶液から分離し、一定分量のイソプロピルアルコールで洗浄した。溶液をデカントした後、粒子をイソプロピルアルコールとリン酸緩衝食塩水(PBS)の混合物で洗浄した。得られた混合物を70%イソプロピルアルコールで3回洗浄した。
(付記1)
少なくとも1つの官能基を含む少なくとも1つのモノマーと、
以下の構造を有する少なくとも1つの架橋剤と、
を含むポリマー粒子。
前記ポリマー粒子は、約40μm〜約1,200μmの直径を有する、付記1に記載のポリマー粒子。
前記ポリマー粒子は、約75μm〜約1,200μmの直径を有する、付記1に記載のポリマー粒子。
前記少なくとも1つの官能基は、アクリレート、アクリルアミド、メタクリレート、またはメタクリルアミドである、付記1に記載のポリマー粒子。
前記少なくとも1つのモノマーは、イオン化官能基を含む、付記1に記載のポリマー粒子。
前記イオン化官能基は、塩基性である、付記5に記載のポリマー粒子。
前記イオン化官能基は、酸性である、付記5に記載のポリマー粒子。
前記少なくとも1つの架橋剤は、少なくとも2つの官能基を含む、付記1に記載のポリマー粒子。
エステル、チオエステル、カーボネート、マトリックスメタロプロテイナーゼによって切断可能なペプチド、マトリックスコラゲナーゼにより切断可能なペプチド、マトリックスエラスターゼにより切断可能なペプチド、およびマトリックスカテプシンによって切断可能なペプチドから選択される第2結合を含む第2架橋剤を有する、付記1に記載のポリマー粒子。
前記ポリマー粒子は、生分解性である、付記1に記載のポリマー粒子。
前記ポリマー粒子は、移植後約1週間以内に実質的に分解される、付記1に記載のポリマー粒子。
前記少なくとも1つのモノマーは、ジメチルアクリルアミドである、付記1に記載のポリマー粒子。
前記少なくとも1つのモノマーは、アクリルアミドである、付記1に記載のポリマー粒子。
少なくとも1つの官能基を含む少なくとも1つのモノマーと、以下の構造を有する少なくとも1つの架橋剤と、油中の開始剤と、を含むプレポリマー溶液を反応させること、および、
ポリマー粒子を形成すること、
を含むポリマー粒子の製造方法。
前記ポリマー粒子は、約40μm〜約1,200μmの直径を有する、付記14に記載の方法。
前記油は、鉱油である、付記14に記載の方法。
前記開始剤は、アゾビスイソブチロニトリルである、付記14に記載の方法。
前記少なくとも1つの官能基は、アクリレート、アクリルアミド、メタクリレート、またはメタクリルアミドである、付記14に記載の方法。
前記ポリマー粒子は、生分解性である、付記14に記載の方法。
前記ポリマー粒子は、移植後約1週間以内に実質的に分解される、付記14に記載の方法。
Claims (20)
- 少なくとも1つの官能基を含む少なくとも1つのモノマーと、
以下の構造を有する少なくとも1つの架橋剤と、
を含むポリマー粒子。
- 前記ポリマー粒子は、約40μm〜約1,200μmの直径を有する、請求項1に記載のポリマー粒子。
- 前記ポリマー粒子は、約75μm〜約1,200μmの直径を有する、請求項1に記載のポリマー粒子。
- 前記少なくとも1つの官能基は、アクリレート、アクリルアミド、メタクリレート、またはメタクリルアミドである、請求項1に記載のポリマー粒子。
- 前記少なくとも1つのモノマーは、イオン化官能基を含む、請求項1に記載のポリマー粒子。
- 前記イオン化官能基は、塩基性である、請求項5に記載のポリマー粒子。
- 前記イオン化官能基は、酸性である、請求項5に記載のポリマー粒子。
- 前記少なくとも1つの架橋剤は、少なくとも2つの官能基を含む、請求項1に記載のポリマー粒子。
- エステル、チオエステル、カーボネート、マトリックスメタロプロテイナーゼによって切断可能なペプチド、マトリックスコラゲナーゼにより切断可能なペプチド、マトリックスエラスターゼにより切断可能なペプチド、およびマトリックスカテプシンによって切断可能なペプチドから選択される第2結合を含む第2架橋剤を有する、請求項1に記載のポリマー粒子。
- 前記ポリマー粒子は、生分解性である、請求項1に記載のポリマー粒子。
- 前記ポリマー粒子は、移植後約1週間以内に実質的に分解される、請求項1に記載のポリマー粒子。
- 前記少なくとも1つのモノマーは、ジメチルアクリルアミドである、請求項1に記載のポリマー粒子。
- 前記少なくとも1つのモノマーは、アクリルアミドである、請求項1に記載のポリマー粒子。
- 少なくとも1つの官能基を含む少なくとも1つのモノマーと、以下の構造を有する少なくとも1つの架橋剤と、油中の開始剤と、を含むプレポリマー溶液を反応させること、および、
ポリマー粒子を形成すること、
を含むポリマー粒子の製造方法。
- 前記ポリマー粒子は、約40μm〜約1,200μmの直径を有する、請求項14に記載の方法。
- 前記油は、鉱油である、請求項14に記載の方法。
- 前記開始剤は、アゾビスイソブチロニトリルである、請求項14に記載の方法。
- 前記少なくとも1つの官能基は、アクリレート、アクリルアミド、メタクリレート、またはメタクリルアミドである、請求項14に記載の方法。
- 前記ポリマー粒子は、生分解性である、請求項14に記載の方法。
- 前記ポリマー粒子は、移植後約1週間以内に実質的に分解される、請求項14に記載の方法。
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US201662401091P | 2016-09-28 | 2016-09-28 | |
US62/401,091 | 2016-09-28 | ||
US201662428990P | 2016-12-01 | 2016-12-01 | |
US62/428,990 | 2016-12-01 | ||
PCT/US2017/054118 WO2018064390A1 (en) | 2016-09-28 | 2017-09-28 | Polymer particles |
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CN103709323A (zh) | 2013-12-04 | 2014-04-09 | 天津工业大学 | 一种肝靶向温敏微球及其制备方法 |
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