JP2011525514A - 活性剤のためのポリマーデリバリーシステム - Google Patents
活性剤のためのポリマーデリバリーシステム Download PDFInfo
- Publication number
- JP2011525514A JP2011525514A JP2011515216A JP2011515216A JP2011525514A JP 2011525514 A JP2011525514 A JP 2011525514A JP 2011515216 A JP2011515216 A JP 2011515216A JP 2011515216 A JP2011515216 A JP 2011515216A JP 2011525514 A JP2011525514 A JP 2011525514A
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- JP
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- Prior art keywords
- block
- copolymer
- formula
- composition according
- oxazoline
- Prior art date
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- Granted
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Abstract
とを含む組成物。
Description
(a) 式(I)
を含む少なくとも一つのコポリマーと;
(b) 1種以上の活性剤
を含む組成物を提供する。
(a)少なくとも一つのブロックAおよび少なくとも一つのブロックBを含む少なくとも一つの生物学的適応性水溶性両親媒ブロックコポリマーであり、Aは親水性ポリ(2−オキサゾリン)類から選択される親水性ポリマーであり、Bは両親媒性もしくは疎水性ポリ(2−オキサゾリン)類から選択される、および
(b)疎水性生物活性化合物
を含み、水中または水性溶液中で可溶性凝集体を形成し、当該凝集体は室温および高温、特に40℃未満の温度で少なくとも12時間安定であり、一般に動物そして特にヒトに前記組成物の非経口投与できる、前記医薬組成物。
医薬組成物は、ペトロラタムのような軟膏に製剤化できる。
ポリマー類の製造のための総ての物質は、Aldrich(Steinheim,Germany)およびAcros(Geel,Belgium)から購入し、特記しない限りそのまま使用した。2−ブチル−2−オキサゾリン(BuOx)は、最近記載された通りにして製造した(Huber,SおよびJordan,R.,Colloid Polym.Sci.286,395−402(2008))。ポリマー製造のためのメチルトリフルオロメチルスルホネート(MeOTf)、2−メチル−2−オキサゾリン(MeOx)、2−エチル−2−オキサゾリン(EtOx)、アセトニトリル(ACN)およびその他の溶媒は、乾燥窒素雰囲気下CaH2上、還流により乾燥し、続いて使用前に蒸留した。室温で、Bruker Avance III 400、Bruker ARX 300またはBruker AC 250に、NMRスペクトルを記録した。このスペクトルを溶媒信号(CDCl3 7.26ppm,D2O 4.67ppm)を使用して調節した(calibrated)。ゲル透過クロマトグラフィー(GPC)をWaters装置(pump.mod.510,RI−検出器 mod.410,予備カラムPLgelおよび2本のPL Resiporeカラム(3μm,300×7.5mm))で、N,N−ジメチルアセタミド(DMAc)(75mmol/L LiBr,80℃、1mL/min)を稀釈剤として用い、PMMA標準に対して調節した。動的光散乱を、Zetasizer Nano−ZS(Malvern Instruments Inc.,Southborough,MA)を使用して室温で行った。
前述した手順にしたがって重合手順および仕上げ手順を行った(Luxenhofer,R.およびJordan,R.,Macromolecules 39,3509−3516(2006);Bonne,T.B.等,Colloid Polym. Sci.282,833−843(2004))。
24mgMeOTf(0.146ミリモル、1eq)、333mgMeOx(3.91ミリモル、27eq、第1ブロック)、286mgBuOx(2.25ミリモル、15eq、第2ブロック)および333mgMeOx(3.91ミリモル、27eq、第3ブロック)および末端用試薬として80μLのピペリジンを使用してP2を得た。無色固体として生成物を得た(795mg、83%、Mth=6.6kg/モル)。
24.7mgメチルトリフレート(0.150ミリモル、1eq)および334mg2−メチル−2−オキサゾリン(3.9ミリモル、26eq、第1ブロック)を使用して、P3を製造した。反応混合物のアリコット136mg(5%w/w)を、NMRおよびGPCを用いて第1ブロックを分析するために取り出した。第2ブロック(364.4mgBuOx;2.87ミリモル、20eq、10%w/w分析した)後、同じ手順を行った。ブロック3(306.9mgMeOx;3.6ミリモル、28eq)を加え、80μLピペリジンを使用して終了させ、無色固体として生成物を得た(598mg、65%、Mth=6.6kg/モル)。
10mgMeOTf(61μモル、1eq)、321mg2−エチル−2−オキサゾリン(EtOx、3.24ミリモル、53eq、第1ブロック)および157mgBuOx(1.23ミリモル、20eq、第2ブロック)、そして末端試薬として150mgピペラジンを使用してP4を製造した。沈殿のため、シクロヘキサンおよびジエチルエーテル(50/50、v/v)の溶媒混合物を使用した。無色固体として生成物を得た(収量0.36g、77%、Mth=7.8kg/モル)。
標準的手順を使用してCMCを決定した。要するに、アセトン(2.5ミリモル)のピレン溶液をバイアルに加え、溶媒を蒸発させた。アッセイバッファ中に適当な濃度のポリマー溶液をバイアルに加え、その結果、5×10−7モルのピレン最終濃度を得た。溶液を25℃でインキュベート(>2時間)し、ピラン蛍光スペクトルをFluorolog3(HoribaJobinYvon)λex=333nm、λem=360〜400nm、スリッド幅(slidwidth)ex=スリッド幅(em)=1nm、ステップ幅0.5nmを使用して記録した。典型的には、各データ点の5スペクトルを平均し(積分時間0.1秒、必要の場合0.2秒積分を用いて10スペクトル)、蛍光強度の急増が観察される場合、CMCが推定される。さらに、I1バンドの蛍光強度をI3バンドの強度と比較した。I3バンドは、ピレンプローブ環境の極性の概算を与える。エクシマーバンド形成は観察されなかった。
4.1 パクリタキセル(PTX)可溶性
薬物−ポリマー溶液を、薄膜法を使用して調製した。適量のポリマーおよびPTX(Sigma−Aldrich,St.Louis,MO,オーダー番号T7191)(ACNまたはエタノール中のストック溶液5〜8mg/mL)を、交互に最小量のACNまたはエタノール中に溶解させた。完全に溶媒を除去させた後、固体ポリマー−薬物フィルムを、アッセイ緩衝液または脱イオン水に入れた。例えば、手順を以下に示す。
薄膜法を使用してシクロスポリンA(Alexis Corporation San Diego,CA、オーダー番号380−002−G001)の可溶化を行った。P2およびシクロスポリンAを使用して、澄明で且つ安定な溶液を得た。
透析による溶媒交換を使用して、アンホテシリンBとP2との可溶化を行った。P2(10.2mg)およびアンホテシリンB三水和物(2.1mg、Riedel−de Haen、Seelze、Germany、オーダー番号46006)を250μLジメチルスルホキシド(DMSO)中に溶解させ、澄明で黄色溶液を得た。総計で750μLの脱イオン水を加えたが、100μL後、混合物は濁った。得られた混合物を透析袋(MWCO 3500g/モル)中に移した。溶液を2L脱イオン水に対して透析した(2時間、4時間および22時間で水を交換した)。総計50時間後、懸濁液(4mL)を透析袋から回収した。500μLアリコットを濾過し(0.45μm)、粒子を除き、澄明黄色溶液を凍結乾燥させ、1mgの黄色泡状固体を得た。残渣を200μL DMSO中に溶解させ、アンホテシリンBを、410nmにおける吸光度を使用して、分光光度法で定量した。透析溶液は366μgのアンホテシリンB(P2に関して18%(w/w))を含有した。別の1mLアリコットを凍結乾燥し(2.2mg黄色発泡体)、続いて、100μL脱イオン水に溶解させた。ポリマー−薬物発泡体は迅速且つ完全に溶解し、低粘度の強黄色溶液を得た。したがって、凍結保護物質を必要としないで、3.7mg/mLのアンホテシリンBが、18.3mg/mLのP2のみを使用して可溶化できた。同じプロトコルを使用して、アンホテシリンBの水溶解度を、約0.4μg/mLであると決定した。
HPLC分析を、等張条件下、SCL−10Aシステムコントローラー、SIL−10A自動注入器、SPD−10AV UV検出器、および2基のLC−10ATポンプを含むSimadzu装置を使用して行った。固定相としてNucleosil C18−5μカラムを使用し(250mm×4mm)、移動相としてアセトニトリル/水混合物(55/45(v/v))を適用した。検出は220nmで行った。ポリマー溶液中のPTXの量を、アセトニトリルに溶解した既知量のPTXを用いて得た較正曲線を使用して計算し、分析をした。
動的光散乱により決定して、薬物添加ミセルは非常に小さいことが見出され(rh=12〜22nm)、狭い寸法分布(PD≒0.04〜0.12)を示す。図3は、P1およびP2(10mg/mL)の薬物添加ミセル(それぞれ、4mg/mL PTX)の動的光散乱の結果を示す。
MCF7/ADR(ドキソルビシンを用いた選択による、ヒト乳癌細胞系、MCF7(ATCC HT−B22)から誘導)を、Y.L.Lee(William Beaumont Hospital、Royal Oak、MI)により提供された。10%熱不活性ウシ胎仔血清(FBS)および別記した1%ペニシリン/ストレプトマイシンを含有するDulbecco’s Modified Eagle’s Medium(DEEM)中に細胞を維持した。Gibco Life Technologies Inc.(Grand Island,NY)から総ての組織物質培地を得た。
総ての実験を、雌性C57/BI/6マウス11〜12週齢(Taconic Laboratories,Germantown、NY)を使用して行った。動物を5匹/ケージに入れ、空気フィルターカバー、光(12時間明/暗サイクル)および温度制御(22F18C)環境下に維持した。動物に関する総ての操作を滅菌ラミナーフード下で行った。食餌および水を自由に与えた。国立衛生研究所により示されたPrinceple of Animal Care and Use Committeにしたがって動物を処理し、プロトコルは、University of Nebaraska Medical CenterのInstitutional Animal Careにより承認された。Lewis肺癌細胞(LLC 3T)をT75フラスコ中で増殖させ、HBSSで採集した。細胞懸濁液(1×106/動物)を右脇腹に50μLの量を皮下注射した。腫瘍出現後、腫瘍寸法を記録し(1日)、10mg/kg PTXの用量で、1、4および7日に100μLの量を注射した。
Claims (18)
- (a) 式(I)
を含む少なくとも一つのコポリマーと;
(b) 1種以上の活性剤と
を含む組成物。 - RAは、各出現に独立して、メチルおよびエチルから選択され、場合により、−OH、−SH、COOH、−NR’2、−COOR’、−CONR’、−CHOで置換されてもよく、R’はHもしくはC1−3アルキルであり、RBはC3−20炭化水素基から選択される、請求項1に記載の組成物。
- RAは、各出現に独立して、メチルおよびエチルから選択され、RBはC4−6アルキル基から選択される、請求項1に記載の組成物。
- コポリマーが、請求項1〜3のいずれかで定義した式(I)の繰り返し単位からなる少なくとも一つのポリ(2−オキサゾリン)ブロックAおよび請求項1〜3のいずれかで定義した式(II)の繰り返し単位からなる少なくとも一つのポリ(2−オキサゾリン)ブロックBを含むブロックコポリマーである、請求項1〜3のいずれかに記載の組成物。
- 少なくとも一つのブロックAはポリ(2−メチル−2−オキサゾリン)またはポリ(2−エチル−2−オキサゾリン)ブロックであり、少なくとも一つのブロックBはポリ(2−ブチル−2−オキサゾリン)ブロックである、請求項4に記載の組成物。
- ブロックコポリマーがABもしくはBAジブロックコポリマーまたはABAもしくはBABトリブロックコポリマーである、請求項4または5に記載の組成物。
- 少なくとも一つの活性剤が疎水性活性剤である、請求項1〜6のいずれかに記載の組成物。
- 少なくとも一つのコポリマーが、活性剤を配合するミセルを形成する、請求項1〜7のいずれかに記載の組成物。
- 活性剤(単味もしくは複数種)対コポリマー(単一もしくは複数種)の重量比が1:10〜1:1の範囲である、請求項1〜8のいずれかに記載の組成物。
- ミセルの寸法が5〜500nmである、請求項8または9に記載の組成物。
- 活性剤とブロックコポリマーとの合計重量に対する活性剤もしくは薬物の重量の比率が10%またはそれ以上である、請求項1〜10のいずれかに記載の組成物。
- 活性剤として薬物を含有する医薬組成物または診断用組成物である、請求項1〜11のいずれかに記載の組成物。
- RAをメチルおよびエチルから選択する上記定義した通りの式(I)の繰り返し単位およびRBがブチルである上記定義した通りの式(II)の繰り返し単位を含むコポリマー。
- ポリ(2−メチル−2−オキサゾリン)またはポリ(2−エチル−2−オキサゾリン)から選択される少なくとも一つのブロックA、およびポリ(2−(C4−6)アルキル−2−オキサゾリン)から選択される少なくとも一つのブロックBを含むブロックコポリマーである、請求項13に記載のコポリマー。
- プラント保護用組成物として、請求項1〜11のいずれかに記載の組成物の使用。
- 水中または水性溶液中に活性剤を可溶化させるための、請求項1〜6、13または14のいずれかに記載のコポリマーの使用。
- 活性化合物の検出方法であって、当該化合物がスクリーニング試験において関心目標と相互作用し、当該方法は、活性化合物を請求項1〜11のいずれかに記載の組成物に配合する工程および得られた組成物を該スクリーニング試験に付す工程を含む、前記検出方法。
- 治療または防止の必要な対象に請求項12に記載の医薬組成物を投与することを含む、障害または疾病を治療または防止する方法。
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US61/134,209 | 2008-07-08 | ||
PCT/EP2009/004655 WO2009156180A2 (en) | 2008-06-26 | 2009-06-26 | Polymeric delivery systems for active agents |
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JP2020512448A (ja) * | 2017-03-14 | 2020-04-23 | フリードリヒ−シラー−ユニバーシタット イエナ | ポリ(オキサゾリン)安定化剤を含有する有機ポリマー粒子および有機ポリマー粒子の安定化のためのポリ(オキサゾリン)の使用 |
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KR20110028372A (ko) * | 2008-07-09 | 2011-03-17 | 보드 오브 리젠츠 오브 디 유니버시티 오브 네브라스카 | 화학 물질의 경조직 표적화 전달을 위한 기능성 마이셀 |
KR101701544B1 (ko) | 2009-06-29 | 2017-02-01 | 벤더 아날리티컬 홀딩 비.브이. | 폴리옥사졸린 및 생리활성제를 포함하는 약물 전달 시스템 |
US9974866B2 (en) | 2010-04-07 | 2018-05-22 | Board Of Regents Of The University Of Nebraska | Protein-poly(2-oxazoline) conjugates for enhanced cellular delivery and transport across biological barriers |
WO2013124867A1 (en) | 2012-02-21 | 2013-08-29 | Amrita Vishwa Vidyapeetham University | Polymer - polymer or polymer - protein core - shell nano medicine loaded with multiple drug molecules |
US20150079007A1 (en) * | 2012-04-20 | 2015-03-19 | Board Of Regents Of The University Of Nebraska | Tunable multimodal nanoparticles and methods of use thereof |
CN103897181B (zh) * | 2012-12-27 | 2017-02-08 | 张昊 | 聚合物、其制备方法和应用 |
WO2014141289A1 (en) | 2013-03-12 | 2014-09-18 | Amrita Vishwa Vidyapeetham University | Photo - chemo composition on the basis of microcapsules with a core -shell structure |
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US20100041592A1 (en) | 2010-02-18 |
JP5671457B2 (ja) | 2015-02-18 |
EP2313115B1 (en) | 2019-05-15 |
RU2523714C2 (ru) | 2014-07-20 |
WO2009156180A2 (en) | 2009-12-30 |
CN102215874A (zh) | 2011-10-12 |
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