JP2020527161A - 注入可能な油中水型エマルション及びその使用 - Google Patents
注入可能な油中水型エマルション及びその使用 Download PDFInfo
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- JP2020527161A JP2020527161A JP2020503016A JP2020503016A JP2020527161A JP 2020527161 A JP2020527161 A JP 2020527161A JP 2020503016 A JP2020503016 A JP 2020503016A JP 2020503016 A JP2020503016 A JP 2020503016A JP 2020527161 A JP2020527161 A JP 2020527161A
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Abstract
Description
本発明によるエマルションは、連続油相(又は脂肪相)を含む。
−炭素原子が16個未満の0.05%〜10%の炭化水素鎖;
−炭素原子が28個を超える0.05%〜5%の炭化水素鎖;
−パラフィン(タイプ)炭化水素鎖の質量とナフテン(タイプ)炭化水素鎖の質量の比に対応する2〜6のP/N比を有する。
本発明によるエマルションは、分散された水相を含む。本発明による水相は、少なくとも水を含む。
本発明の水相は、少なくとも1つのポリエステルベースのナノ粒子を含む。
本発明によるエマルションは、少なくとも1つの治療薬を含む。
PLGAナノ粒子は、すでに文献に開示されているエマルション蒸発法に従って調製された(Astete,C E;Sabliov,C M Synthesis and Characterisation of PLGA Nanoparticles.J.Biomater.Sci.Polym.Ed.2006,17(3),247−289)。100mgのPLGAを5mlのジクロロメタンに溶解し、2.5mg/mlのPVAを含む水溶液20 mlで1分間、40%の力で超音波処理(VibraCell sonicator, Fisher Scientific, France)により乳化した。次に、有機溶媒を周囲温度で、磁気撹拌しながら2時間蒸発させた。蒸発後、NPを超遠心分離(LE−80K Ultracentrifuge Beckman Coulter Optima(商標))により4℃、37,000gで1時間精製した。上清を除去した後、NPを50mg/mlのトレハロース(凍結防止剤)を含む水溶液に再び懸濁した。次に、NPの懸濁液を凍結乾燥した。使用前に、凍結乾燥されたNPは、MilliQ水に目的の濃度で再分散された。
エマルションは、3ウェイストップコックを介して2つの10mlシリンジを70秒間繰り返し、ポンピング(70プッシュ−プルサイクル)することで、リピオドール(Guerbet,France)/生理食塩水比3/1(v/v)で調合された。最初のシリンジにはリピオドールが含まれ、2番目のシリンジは空であり、3番目のシリンジに配置された生理食塩水は、シリンジポンプを介して流量1mL/分でシステムに徐々に導入される。水相は、生理食塩水中の様々な濃度のナノ粒子の懸濁液である(図1を参照)。
エマルションは、可変リピオドール/生理食塩水比で15mg/mlナノ粒子の濃度で、実施例1と同じプロトコールに従って製剤化された(図2を参照)。
各エマルションについて、エマルションの種類(油中水又は水中水)を、リピオドール(先にスーダン赤で着色)と生理食塩水(先にメチレンブルーで着色)を含む2つの溶液を使用した比色試験により決定した。溶液の1つの小さな液滴を、試験したエマルションの液滴に追加した。エマルションの連続相は、溶液の液滴とエマルションの液滴が最終的に混和する可能性を観察することで明らかになった。乳化直後に試験を実施した。
エマルションは、Turbiscan(登録商標)MA 2000(Formulation,L’Union,France)を使用して分析した。エマルションを含むチューブは、システムからの外乱を避けるために、デバイスから取り外したり、測定の終了まで触れたりしなかった。測定は、システムの進化に応じて所定の時間に実行された。この監視は、強度の変化が無視できるようになるまで行われた。Turbiscan装置を使用すると、希釈せずにサンプルの可逆的(クリーミングと沈降)及び不可逆的(コアレッセンスと偏析)の不安定化現象を測定できる(図3及び4)。
エマルションの注入性は、テクスチャアナライザー(TA−XT2、Texture Technologies)を使用して調査した。測定は、血管マイクロカテーテル(直径:2.4 F)又は18ゲージ針のいずれかに接続された1mlの「Medallion」シリンジ(Merit(登録商標))を使用して実行された。様々な油/水の比率(8/3、3/1、及び6/1)が2mm/sの速度で研究され、3/1の比率については、様々な注入率が試験された。油のみ(リピオドール)をコントロールとして使用した(図5)。
エマルションは、実施例2と同じプロトコールに従って製剤化された。水相は、エマルションの製剤化のために生理食塩水(Adriblastine,Pfizer,USA)で10又は20mg/mlの濃度で再構成された塩酸ドキソルビシンからなる。エマルションは、異なるリピオドール/ドキソルビシン比、異なる濃度のドキソルビシン及び異なる濃度のナノ粒子を使用して製造された(以下の表1を参照)。
分析は、実施例5で使用したプロトコールに従って実行された。様々なエマルションのクリーミングは、Turbiscanで迅速に観察されたが、24時間監視しても相分離はなかった(図6)。
エマルションは、実施例2と同じプロトコールに従って製剤化された。水相は、抗体(5mg/mlのIpilimumab、Yervoy、Bristol Myers Squibb)から構成される。エマルションは、15mg/mlのナノ粒子濃度で3/1のリピオドール/イピリムマブ比で製造された。
3/1の比を有し、20mg/mlの濃度でドキソルビシンを充填したリピオドール化エマルションからのドキソルビシンの生体外放出(2種類:ナノ粒子なし、15mg/ml濃度のナノ粒子あり)又はドキソルビシンを充填したビーズから25mg/ml(DCビーズ、生体適合性サイズ300−500μm)の濃度が評価された。0.8mLのエマルション(4mgのドキソルビシンに相当)又は0.16mLのビーズをGeBAflexチューブ(カットオフ:12−14kDa;GeneBio−ApplicationLtd)に導入した。これらのチューブを40mlの緩衝生理食塩水(TRIS、pH7.4)に浸し、37℃、150rpmのインキュベーターに入れた。事前に決められた時間に、アリコート(80μL)を収集し、同量のTRISで置き換えた。
エマルションは、実施例2と同じプロトコールに従って製剤化された。水相は、イリノテカン(塩酸イリノテカン三水和物、20mg/mL;Campto(登録商標)、ファイザー)で構成される。
エマルションは、実施例2と同じプロトコールに従って製剤化された。水相は、オキサリプラチン(Eloxatin(登録商標)、5mg/mL、Sanofi−Aventis)から構成される。
エマルションは、実施例2と同じプロトコールに従って3/1の比率で製剤化された。水相は、20mg/mLの濃度の生理食塩水又はドキソルビシンのいずれかで構成される。油相は、オリーブ油、ゴマ油、ヒマシ油、ケシの実油又はミグリオールのいずれかで構成される。すべてのエマルションは、15mg/mlの濃度のナノ粒子で調合される。
ポリ(乳酸−co−グリコール酸)−酸化鉄[PLGA−FeO]ナノ粒子は、実施例1で説明したのと同じ方法に従って調製された。オレイン酸(25mg/mL、サイズ10nm、Ocean、USA)で装飾されたFe3O4ナノ粒子の500μL溶液を5mLのジクロロメタンに事前に溶解した100mgのPLGAに加え、2.5mg/mLのPVAを含む20mLの水溶液で超音波処理(VibraCell sonicator、Fisher Scientific、フランス)で40%の力で1分間乳化した。次に、有機溶媒を周囲温度で、磁気撹拌しながら2時間蒸発させた。蒸発後、懸濁液を3000rpmで5分間遠心分離し、上清を除去し、ペレットを脱イオン水で濯いだ。遠心分離プロセスを2回繰り返した。次に、NPを超遠心分離(LE−80K Ultracentrifuge Beckman Coulter Optima(商標))で4℃、37,000gで1時間精製した。上清を除去した後、NPを50mg/mlのトレハロース(凍結防止剤)を含む水溶液に再び懸濁した。次に、NPの懸濁液を凍結乾燥した。使用前に、凍結乾燥されたNPは、MilliQ水に目的の濃度で再分散された。
エマルションは、異なる濃度のPLGA−FeOナノ粒子(20、15、又は10mg/mL)で、実施例2と同じプロトコールに従って製剤化された。エマルションは、比色試験による油中水型である。
エマルションは、実施例2と同じプロトコールに従って、ドキソルビシン20mg/ml及びPLGA−FeOナノ粒子15g/mLの濃度で製剤化された。油中水型エマルションが得られた。
エマルションの微視的構造は、WLLレーザー(488及び563nmの励起波)及びCS263x/1.40液浸対物レンズを備えた共焦点レーザー走査顕微鏡(LeicaTCSSP8−STED、ドイツ)によって観察された。エマルションの液滴の変形を防ぐために、サンプルを湾曲したスライドガラスに載せた。PLGA−FeOナノ粒子を使用して、エマルションを製剤化して、透過状態で見ることができるようにした(ドキソルビシンの発光スペクトルとの干渉効果を回避する)。ドキソルビシンの蛍光は、590nmのレーザー照射下で600〜710nmのフィルターで観察された。赤色蛍光発光は連続モードで収集された。
この画像診断法が腫瘍ファントムに含まれる油の比率を定量化する目的に効果的に機能することを確認するために、エマルションをMRIで評価した。
エマルションは、実施例2と同じプロトコールに従って製剤化された。水相は、供給業者が推奨する治療濃度で以前に再構成された活性成分から構成されるか、又は市販形態の濃度の水溶液中の活性成分から直接構成される。エマルションは、ナノ粒子の濃度15mg/mlで、溶液比3/1のリピオドール/有効成分に基づいて製造された。
液滴のサイズの測定は、画像解析技術(Flowcell FC200S+HR、Occhio、ベルギー)を使用して粒子カウンターで行った。まずエマルションを油で20倍に希釈し、次に分析用に0.5mLの希釈エマルションを400μmのスペーサーを通して導入する。各サンプルは、生理食塩水とイピリムマブを含むサンプルについて、(日)D7と異なる日(D0、D7、D35)に少なくとも4回測定された。計算は少なくとも500ドロップで行われた。
エマルションは、実施例9と同じプロトコールに従って製剤化された。リピオドール化エマルションからのイピリムマブのインビトロ放出(3/1比、ナノ粒子の濃度15mg/mL)を評価した。1mgのイピリムマブに対応する0.8mLのエマルションを20 mLの緩衝生理食塩水(PBS、pH7.4)を含むチューブに入れ、37℃にて150rpmの速度でインキュベーターに入れた。所定の時間に、アリコート(300μL)を収集し、等量のPBSで置き換えた。放出されたイピリムマブの量は、BCA(ビシンコニン酸)タンパク質アッセイ法:ビシンコン酸に基づく比色タンパク質アッセイにより定量された(図13)。
この研究のためのエマルションは、実施例12と同じプロトコールに従って製剤化された。
グループ1:ナノ粒子で安定化されていない従来のオキサリプラチンエマルションを投与されたウサギ。このグループは注射の1時間後に安楽死させた(n=4)
グループ2:ナノ粒子で安定化されたオキサリプラチンエマルションを投与されたウサギ。このグループは注射の1時間後に安楽死させた(n=5)
グループ3:ナノ粒子で安定化されていない従来のオキサリプラチンエマルションを投与されたウサギ。このグループは、注射の24時間後に安楽死させた(n=4)
グループ4:ナノ粒子で安定化されたオキサリプラチンエマルションを投与されたウサギ。このグループは注射の24時間後に安楽死させた(n=5)。
2種類のエマルションの注入後のオキサリプラチンの薬物動態を表4及び図14にまとめる。ピカリングエマルションの注入後のオキサリプラチンの血漿ピーク(Cmax)は、従来のエマルション(0.49±0.14ng/mL対1.08±0.41ng/mL、p<0.01)と比べて有意に低い、1時間での曲線下面積(AUC)は、ピカリングエマルションの方が有意に低い(19.8±5.9対31.8±14.9、p=0.03)。
組織中のオキサリプラチンの濃度を表4及び5に示す。24時間では、ピカリングエマルションを使用した場合、腫瘍/左葉の比率は従来のエマルションと比較して有意に高い(43.4±42.9対14.5±6.6、p=0.04)。
Claims (14)
- 連続油相と、液滴の形態で分散された水相とを含む油中水エマルションであって、前記水相がポリエステルベースのナノ粒子と少なくとも1つの治療薬とを含む上記油中水エマルション。
- 油相が、特に脂肪酸、脂肪酸エステル及び鉱油から選択される少なくとも1つの油を含む、請求項1に記載のエマルション。
- 油相が、少なくとも1つの植物油、特にヒマシ油、ゴマ油、ケシ油、オリーブ油、大豆油、ヤシ油、トリオレイン、及びそれらの混合物を含む、請求項1又は2に記載のエマルション。
- 油相が、ケシ種子油からのヨウ素化脂肪酸のエチルエステル、8〜12個の炭素原子を含む中鎖長を有するトリグリセリド、又は主にスクアレンで構成される鉱油を含む、請求項1〜3のいずれか1項に記載のエマルション。
- 水相の液滴のサイズが10μm〜100μmである、請求項1〜4のいずれか1項に記載のエマルション。
- 前記ポリエステルベースのナノ粒子が、ポリ乳酸(ポリラクチド)、ポリグリコール酸(ポリグリコリド)、ラクチド−グリコリドコポリマー、ラクチド−グリコリド−co−ポリエチレングリコールコポリマー、ポリオルトエステル、ポリ無水物、ポリブチルアセトン、ポリバレロラクトン、ポリリンゴ酸、ポリラクトン、及びそれらの混合物に基づくナノ粒子からなる群から選択される、請求項1〜5のいずれか1項に記載のエマルション。
- 治療薬が、免疫調節剤、抗癌薬製品、抗血管新生薬製品、抗感染薬製品、抗炎症薬製品、造影剤、放射性物質及び感染性物質から選択される、請求項1〜6のいずれか一項に記載のエマルション。
- 抗癌性医薬品が、アルキル化剤、白金誘導体、細胞毒性抗生剤、抗微小管剤、アントラサイクリン、トポイソメラーゼI型及びII型阻害剤、フルオロピリミジン、シチジン類似体、アデノシン類似体、メトトレキサート、フォリン酸、酵素、抗血管剤、抗血管新生剤、抗有糸分裂剤、キナーゼ阻害剤、ホルモン、モノクローナル抗体、放射性元素、腫瘍溶解性ウイルス、及びそれらの混合物からなる群から選択される、請求項7に記載のエマルション。
- 治療薬が、ドキソルビシン、イリノテカン、オキサリプラチン、及びそれらの混合物からなる群から選択される抗癌性医薬品である、請求項1〜8のいずれか1項に記載のエマルション。
- 治療薬が、抗血管新生モノクローナル抗体、抗CTLA−4モノクローナル抗体、抗PD−1モノクローナル抗体、抗PD−L1モノクローナル抗体、及びそれらの混合物からなる群から選択される、請求項7に記載のエマルション。
- 前記ポリエステルベースのナノ粒子が酸化鉄粒子をさらに含む、請求項1〜10のいずれか1項に記載のエマルション。
- 請求項1〜11のいずれか1項に記載のエマルションを含むことを特徴とする医薬品。
- 請求項1〜11のいずれか1項に記載のエマルション、ならびに少なくとも1つの薬学的に許容される賦形剤を含む医薬組成物。
- 癌の治療に使用するための、請求項8〜10のいずれか1項に記載のエマルション。
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CA3068905A1 (fr) | 2019-01-24 |
CN111263632A (zh) | 2020-06-09 |
US20210113463A1 (en) | 2021-04-22 |
AU2018304530A1 (en) | 2020-01-30 |
EP3654937A1 (fr) | 2020-05-27 |
IL271898A (en) | 2022-01-01 |
AU2018304530B2 (en) | 2024-02-15 |
KR20200032092A (ko) | 2020-03-25 |
JP7247164B2 (ja) | 2023-03-28 |
WO2019016138A1 (fr) | 2019-01-24 |
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