JP6700634B2 - 油性組成物 - Google Patents
油性組成物 Download PDFInfo
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- JP6700634B2 JP6700634B2 JP2016542342A JP2016542342A JP6700634B2 JP 6700634 B2 JP6700634 B2 JP 6700634B2 JP 2016542342 A JP2016542342 A JP 2016542342A JP 2016542342 A JP2016542342 A JP 2016542342A JP 6700634 B2 JP6700634 B2 JP 6700634B2
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- lipiodol
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- 239000005720 sucrose Substances 0.000 description 1
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Description
a)複数の塞栓粒子を提供するステップと、
b)Lipiodolと塞栓粒子との混合物を形成するべく塞栓粒子をLipiodolと接触させるステップと、
c)好ましくは安定なエマルジョンを提供するためにLipiodolと塞栓粒子との混合物を水性組成物(通常、医薬品活性成分を含む)と乳化させるステップと、
を含むプロセスを提供する。
Ci)Lipiodol:水性相の比が体積比(vol/vol)で1以上:1であるように水性相の体積を調整するステップと、
Cii)水性相の比重を1.15から1.35までの間に調整するステップと、
Ciii)油の比重を粒子の比重と適合させるステップと、
Civ)油の比重を水性相の比重と適合させるステップと、
Cv)粒子の比重を水性相の比重と適合させるステップと、
のうちの1つ以上を含んでもよい。
a)塞栓粒子を提供するステップと、
b)塞栓粒子をLipiodolと接触させるステップと、
c)粒子とLipiodolとの組成物を、医薬品活性成分を含む水性組成物と接触させるステップと、
を含むプロセスである本発明のさらなる態様を提供する。
a)複数の乾燥した塞栓粒子を提供するステップと、
b)Lipiodolと塞栓粒子との混合物を形成するべく乾燥した塞栓粒子をLipiodolと接触させるステップと、
c)Lipiodolと塞栓粒子との混合物を、塞栓粒子を少なくとも部分的に再水和させるのに十分な医薬品活性成分の水性溶液と接触させるステップと、
d)塞栓組成物を提供するべく塞栓粒子に水性溶液を取り込ませるステップと、
を含む、プロセスを提供する。
a)本明細書に記載のエマルジョン又は油組成物を提供することと、
b)組織を塞栓するべくエマルジョン又は油組成物を前記血管に送達することと、
を含む方法を提供する。
実施例1
乾燥塞栓ビーズの調製: 市販のPVA−AMPSヒドロゲルマイクロビーズ(英国ファーナムのBiocompatibles UK Ltd製のLC Bead(登録商標)であり、8mlの1mMリン酸緩衝生理食塩水(PBS)中に2mlのビーズ充填体積(100〜300um))を、懸濁媒質から取り出し、10%のD−マンニトール中に再び懸濁させた。平衡後に、吸引により上澄みを除去し、ビーズを凍結乾燥した。ビーズの第2のバッチを、マンニトールなしに上記のように凍結乾燥した。
Lipiodol中の塞栓ビーズの懸濁:
サンプル1.実施例1のように調製した凍結乾燥されたマンニトール・乾燥塞栓ビーズのバイアルに4mlのLipiodol Ultra Fluide(Guerbet(Lipiodol))を入れて穏やかに振とうすることで再び懸濁させ、Lipiodolを吸収させるために数分間立てておいた。
サンプル2.LC−Bead(登録商標)(100〜300um)の1つのバイアルから充填溶液(packing solution)を完全に除去した。4ミリリットルのLipiodolを加え、穏やかに振とうすることで混合させた。残っている水とLipiodolとの相分離が、ビーズの群と共にすぐに観察された。
顕微鏡検査により、凍結乾燥ビーズ(サンプル1)は、透明で、Lipiodol中に均一に分散されることが観察された。サンプル2からのビーズは、ほぼすべて水相に存在することが分かった。
ビーズのロード:実施例2からの各サンプルに2mlの25mg/mlドキソルビシン溶液を加え、穏やかに撹拌した。
マンニトール・乾燥ビーズ(サンプル1)は、ほとんどすべてのドキソルビシン溶液を迅速に吸収し、Lipiodol層から分離されるスラリーを形成した。ビーズ相のサンプルは、明るい赤色のビーズと所々の小さい水滴を示した。
しかしながら、サンプル2の調製物は、下側の油相、中間のドキソルビシンビーズ層、及び減ったドキソルビシン溶液の上層との3層に分離した。
次いで、サンプル1及び2からのビーズのサンプルを、或る体積の脱イオン水の表面よりも下に穏やかにピペットで入れた。サンプル2のビーズの多くは水中に沈む際に分散し、血液中に分散する傾向を示し、一方、サンプル1のビーズ(凍結乾燥ビーズで作製)は油中水滴の底に沈み、分散しなかった。
エマルジョン: Omnipaque 350(GE Healthcare−Omnipaque))を水と50:50で混合し、4mlのこの溶液を実施例3からの各バイアルに加えた。次いで、各バイアルの中身を20mlのシリンジに移し、すべての空気を除去した。エマルジョンを、乳化の特徴的な音が止むまで三方ステンレス鋼活栓を通じて2つの20mlのシリンジ(BD Luer−Lok(登録商標)Tip)間を往復通過させることによって調製し、なめらかな安定なエマルジョンを形成した。これは、およそ20回の通過を必要とした。
或る体積のエマルジョンを、針を通じて脱イオン水の表面よりも下に穏やかに分与した。ビーズは、サンプル2(DCビーズ)から調製されたエマルジョンから1〜2分以内に分散し始めたが、マンニトール・乾燥ビーズで調製されるサンプル1から調製されたエマルジョンからはそうではなかった。
PVA−AMPSヒドロゲル塞栓ビーズのロード速度に対するLipiodolの影響の観察: 10mlのLipiodolを、実施例1に従って調製した乾燥ビーズ(100〜300um、マンニトール・乾燥ビーズとマンニトールなし・乾燥ビーズとの両方)の1つのバイアルに加えた。バイアルを10分間放置した。lipiodolを乾燥ビーズにロードすると、バイアルに2mlの25mg/ml塩酸ドキソルビシン溶液を加え、少しの間穏やかに混合した。水性相を5μlずつ定期的に除去し、水で1mlに希薄した。Lipiodolを除去しないように注意した。実験をLipiodolが存在しない状態で繰返した。
上記の乾燥ビーズ調製物を、水和ビーズを用いる類似の調製物と比較した。DCビーズ(100〜300um)のバイアルから充填溶液を吸引により除去した。10ミリリットルのLipiodolを加え、ビーズと穏やかに混合し、混合物を10分間放置した。バイアルに2ミリリットルの25mg/mlドキソルビシンを加えた。5μlずつ除去し、前述のように分析評価した。実験をLipiodolが存在しない状態で繰返した。
希薄したサンプルの483nmでの吸光度を測定し、ビーズによる最大吸収%に変換した。
Lipiodolエマルジョンの調製
A.実施例1に従って調製した乾燥ビーズ(100〜300um)の1つのバイアルに10mlのLipiodolを加えた。穏やかな混合及び平衡後に、2mlの25mg/ml塩酸ドキソルビシン溶液と6mlのOmnipaque(登録商標)350を加えた(水性相の密度1.27)。組成物を、三方タップを通じて20mlのシリンジと5mlのシリンジとの間で20回迅速に通過させることによって乳化させた。顕微鏡検査は、水相中にドキソルビシンをロードしたビーズを有する油中水型エマルジョンを示した。
B.DCビーズの1つのバイアルから充填溶液を除去し、10mlのLipiodolで置換した。次いで、2mlの25mg/ml塩酸ドキソルビシンを加えた。ビーズは、すぐに薬剤を取り込み始めた。振とう後に、6mlのOmnipaque350を加え、組成物を上記のように2つのシリンジ間で激しく混合した。顕微鏡検査は、水相中にドキソルビシンをロードしたビーズを有する油中水型エマルジョンを示した。
C.40〜90umのサイズ範囲のビーズ: PVA−AMPS塞栓ビーズを、米国特許第7,442,385号の実施例1の高AMPS処方に従って調製し、直径40から90umの間のビーズを提供するためにふるいにかけた。保管のための8mlの1mM滅菌リン酸緩衝生理食塩水中に2mlの充填体積のビーズを提供するべくビーズを分取した。使用のために、PBS貯蔵溶液を吸引し、次いで、ビーズを、そのままで用いるか、又は実施例1のようにマンニトール乾燥ビーズを調製するのに用いた。
D.40〜90umのマンニトール乾燥ビーズを用いるエマルジョン: 上記のCに従って調製したマンニトール・乾燥ビーズ(40〜90um)の1つのバイアルに10mlのLipiodolを加え、均一な懸濁を提供するべく混合した。平衡後に、2mlの25mg/ml塩酸ドキソルビシン溶液を加え、その後、6mlのOmnipaque(登録商標)350を加えた。ビーズは、ほとんどすべてのドキソルビシン溶液を保持した。混合後に均一な懸濁が見られ、これは2分後に沈降した。2mlのさらなる水を加え、混合物を20mlのシリンジに移した。組成物を前述のように乳化させた。エマルジョンは7〜8分間安定であった(すなわち、この時点で相の分離が最初に認められた)。
E.40〜90umの水和ビーズを用いるエマルジョン: このエマルジョンはOmnipaqueが存在しない状態で調製した。上記のCに従って調製した40〜90umビーズの1つのバイアルから充填溶液を除去し、10mlのLipiodolを加えた。均一な懸濁を形成するべくビーズをLipiodolと混合し、2mlの25mg/mlドキソルビシンを加えた。エマルジョンを上記のように調製した。相分離の開始が4分後に観察された。
Lipiodolエマルジョンと塞栓粒子を含有するエマルジョンとの比較
Lipiodolエマルジョンを以下のように調製した。10mlのLipiodolを20mlのシリンジに入れた。次いで、2mlの塩酸ドキソルビシン溶液(25mg/ml)を入れ、その後、6mlのOmnipaqueを入れた。なめらかなエマルジョンをもたらすべく三方コネクタ(BD Connecta)を通じて5mlのシリンジとの間で往復(20回)させることによってすべての3つの成分をよく混合した。
実施例1に従って調製したマンニトール・乾燥ビーズ又は水和DC−ビーズのいずれかを組み込んで実験を繰返した。
実施例1に従って調製した乾燥ビーズ(100〜300um)のバイアルに、10mlのlipiodolを加え、Lipiodol中のビーズの懸濁を提供するためによく混合した。バイアルを10分間放置した。Lipiodolをビーズにロードすると、2mlの塩酸ドキソルビシン(25mg/ml)を加え、薬剤のロードのためにバイアルを5分間放置した。薬剤のロード後に、バイアルに6mlのOmnipaqueを加えた。次いで、バイアルのすべての成分を20mlのシリンジに移し、なめらかなエマルジョンを得るべく前述のように乳化させた。
DCビーズ(100〜300um)のバイアルからの充填溶液の完全除去後に、10mlのLipiodolを加え、Lipiodol中のビーズの懸濁を提供するべくよく混合した。次いで、バイアルを10分間放置した。DCビーズは、およそ95%の水を含むヒドロゲルである。2mlの充填体積のビーズを含むバイアルにおいて、間隙の充填溶液が除去されるときの水の体積はおよそ0.9mlである。
10分後に、2mlの25mg/ml塩酸ドキソルビシン溶液を加えた。次いで、バイアルの中身を20mlのシリンジに移し、シリンジに6mlのOmnipaqueを加え、中身を前述のように乳化させた。
乳化後に、各シリンジを先端が上を向くように直立させ、次の50分にわたって観察した。
Lipiodolエマルジョンは、相分離が観察されない状態で50分にわたって安定なままであった。
乾燥ビーズで作製されるエマルジョンを保持するシリンジにおいて、相分離は、15分後に調製物の頂部及び底部でのみ見られ、20分後には明らかであり、一方、水和ビーズで作製されるバイアルにおいて、相分離の開始は7分後に明白であった。表1は観察のまとめである。
それぞれからの最初のサンプルを、Terumo2.4Frカテーテルを通じてpH7.4の或る体積のリン酸緩衝生理食塩水の表面よりも下に導入した。標準Lipiodolエマルジョンは、迅速に散ってドキソルビシンを溶液中に放出した。マンニトール・乾燥ビーズを用いて調製されたエマルジョンは、表面よりも下に液滴として残り、非常にわずかなビーズが液滴から分離した。DCビーズを用いて調製されたエマルジョンも液滴として残ったが、はるかにより多くのビーズが生理食塩水中に分散した。
エマルジョンからのドキソルビシンの溶離の比較
室温でpH7.4の400mlのリン酸緩衝生理食塩水(PBS)と磁気撹拌子が入っているビーカーを用意した。ビーカーをマグネチックスターラ上に置いた。エマルジョンを実施例7に従って調製し、完成したサンプルを生理食塩水の表面よりも下にすぐに穏やかに導入し、穏やかな撹拌を開始した。PBSの5mlのサンプルを或る間隔で除去し、新しいPBSで置換した。どのようなLipiodol汚染も分離するべくサンプルを遠心分離し、サンプル中のドキソルビシンの濃度を483nmでの吸光度によって求めた。図2は、最初の2時間にわたるドキソルビシンの溶離を示す。
存在したほとんどすべてのドキソルビシンは、標準Lipiodolエマルジョンから非常に迅速に溶離した。同じ時間でビーズを含むエマルジョンからはるかに少ないドキソルビシンが溶離した。
10mlのLipiodolを2.2〜2.3mlの乾燥PVA−AMPSビーズ(マンニトールなし、サイズ70〜150um)と混合し、シリンジに移した。この組成物に、lipiodolと水性相との種々の比及び水性相の比重を提供するべくドキソルビシン溶液(25mg/ml)と造影剤(Omnipaque 350、比重1.406)を混合した。ビーズ/Lipiodol組成物に最初にドキソルビシン溶液を加え、ドキソルビシンの大部分がビーズに取り込まれるまで穏やかに混合した(40分間、ドキソルビシンのおよそ80%がビーズに取り込まれた)。
前述の2つのシリンジ間での激しい混合後に、lipiodol相の25%が沈降するのにかかる時間(安定性の尺度)を測定するためにシリンジを直立した状態に保った。それぞれからのサンプルを、Terumo 2.4Frカテーテルを通じてpH7.4の或る体積のリン酸緩衝生理食塩水の表面よりも下に導入し、エマルジョンの挙動の観察を行い、以下のスキームに従ってスコア付けした。
Claims (20)
- 水性相及び油性相を含むエマルジョンの形態の、ハロゲン化油と水溶性ではなく、水で膨潤可能なヒドロゲルポリマーを含む1つ以上の塞栓粒子とを含む医薬品組成物であって、前記組成物は油中水型エマルジョンの形態であり、前記塞栓粒子は親水性である、医薬品組成物。
- 前記ハロゲン化油がLipiodol(登録商標)である、請求項1に記載の医薬品組成物。
- 前記塞栓粒子が医薬品活性成分を含む、請求項1又は請求項2に記載の医薬品組成物。
- 前記油相及び/又は前記水性相中に医薬品活性成分を含む、請求項1〜請求項3のいずれか1項に記載の医薬品組成物。
- 前記油相中に溶解される疎水性の医薬品活性成分を含む、請求項4に記載の医薬品組成物。
- 前記Lipiodolと水性相との比が、体積比(V/V)で1以上(Lipiodol):1(水性相)である、請求項1〜請求項4のいずれか1項に記載の医薬品組成物。
- 前記水性相の比重が1.15から1.35までの間である、請求項1〜請求項6のいずれか1項に記載の医薬品組成物。
- 前記粒子の比重が1.0から1.5までの間である、請求項1〜請求項7のいずれか1項に記載の医薬品組成物。
- 前記塞栓粒子が、PVAポリマーを含む、請求項1〜請求項8のいずれか1項に記載の医薬品組成物。
- 前記PVAポリマーが架橋化PVAである、請求項9に記載の医薬品組成物。
- 前記架橋化PVAがPVA−AMPSである、請求項10に記載の医薬品組成物。
- 前記ポリマーがPVA co−アクリル酸ナトリウムを含む、請求項1〜請求項9に記載の医薬品組成物。
- Lipiodolと塞栓粒子との比が100:1から1:1vol/volまでの間である、請求項1〜請求項12のいずれか1項に記載の医薬品組成物。
- 水溶性ではなく、水で膨潤可能なヒドロゲルポリマーを含む複数の塞栓粒子、ハロゲン化油、及び水性相を提供することと、エマルジョンを提供するべくそれらを乳化させることを含む、油中水型エマルジョンの形態である医薬品エマルジョンを調製するためのプロセス。
- 請求項14に記載の医薬品エマルジョンを調製するためのプロセスであって、
a)水溶性ではなく、水で膨潤可能なヒドロゲルポリマーを含む複数の乾燥した塞栓粒子を提供するステップと、
b)ハロゲン化油と塞栓粒子との混合物を形成するべく前記乾燥した塞栓粒子をハロゲン化油と接触させるステップと、
c)前記ハロゲン化油と塞栓粒子との混合物を医薬品活性成分の水性溶液と接触させるステップと、
d)前記c)の組成物を乳化させるステップと、
を含む、プロセス。 - 組織を塞栓する方法で用いるための請求項1〜請求項13のいずれか1項に記載の組成物。
- 請求項14又は請求項15のいずれか1項に記載の方法によって調製される医薬品組成物。
- 封止された容器内に、水溶性ではなく、水で膨潤可能なヒドロゲルポリマーを含む複数の塞栓粒子を含む滅菌された調製物と、前記組成物をどのようにして調製するかについての使用説明書とを含む、請求項1に記載の医薬品組成物を調製するためのキット。
- 前記塞栓粒子が乾燥した塞栓粒子である、請求項18に記載のキット。
- 前記粒子が、1mM滅菌リン酸緩衝生理食塩水で十分に水和されるときに1から5mlまでの間の充填体積をとる乾燥した塞栓粒子である、請求項18又は請求項19に記載のキット。
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