JP6165920B2 - 活性成分のポリマーコンジュゲート、その製造方法及びそのポリマー中間体 - Google Patents
活性成分のポリマーコンジュゲート、その製造方法及びそのポリマー中間体 Download PDFInfo
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
- C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
- C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
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- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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- A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
- A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
- A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
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Description
−mPEGはメトキシ−ポリエチレングリコールであり、
−PLAはポリ乳酸であり、
−mはポリエチレングリコール断片(mPEG)の平均分子量であり、100から15000(Daで表示)、特に100〜10000、より特に1000から5000の範囲であり、例えば約2000であり、
−nはポリ乳酸断片の平均分子量であり、1000から50000(Daで表示)、より特に3000から20000、更により特に5000から20000の範囲から選択され、例えば約10000または14000であり、
−APは好ましくはタキソイドから選択される活性成分残基であり、
−Lはリンカーであり、
−Xは水素原子、または場合によりハロゲン原子、或いはOR、CN、CF3、NRR’またはCOOR基から選択される1個以上の置換基で置換されているアルキル基であり、ここでR及びR’は同一であるかまたは相互に異なっており、水素原子またはアルキル基である。
(式中、AP、X、L、p及びqは上に定義した通りである)
−ハロゲン原子はフッ素、塩素、臭素またはヨウ素を意味すると理解される;
−アルキル基は飽和の線状または分岐状(C1−C6)脂肪族炭化水素基を意味すると理解される。例として、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、tert−ブチルまたはペンチル基等が挙げられ得る;
−アリール基は5から10個の炭素原子を含む芳香族環式基を意味すると理解される。アリール基の例としてフェニルまたはナフチルが挙げられ得る。
の化合物からリンカーLHの前駆体とカップリングすることにより得られ得る。よって、LHがジスクシネート基を表す場合には、使用される前駆体は無水コハク酸である。Lがジグリコレート基の場合には、使用される前駆体は無水ジグリコール酸である。所望されるL基に従って利用される前駆体は通常当業者に公知であり、市販されている。
1.式(IV):
2.こうして得たモノ保護されている化合物を(PLA)n基の前駆体とカップリングする段階;
3.段階1で導入した保護基を脱保護する段階;
を含む。
の化合物から、保護基Pg1及びPg2を特に接触水素化Pd/Cまたは酸性加水分解により脱保護することにより得られ得る。
Avance 500MHzデバイスを用いて周囲温度で記録する。1H及び13Cにおける化学シフトδは残留溶媒に対してppmで報告し、29Siにおける化学シフトδは外部標準としてのMe4Siに対してppmで報告する。カップリング定数Jはヘルツで示す。シグナルを示すために以下の略号が使用されている:s(一重項)、br(広幅)、d(二重項)、t(三重項)、q(四重項)及びm(多重項)。
HS(Malvern)を用いてDLSにより測定する。
抽出する。
ルゴン下35℃で撹拌する。6時間後、無水酢酸(166μl,1.71mmol)及び4−ジメチルアミノピリジン(DMAP)(4.5mg,0.35mmol)を反応媒体に添加する。後者を更に1時間撹拌する。その後、混合物を真空下で濃縮し、次いで0℃でMeOH(150ml)から沈殿させる。形成された白色沈殿を濾別し、MeOH(20ml)で洗浄し、次いで真空下で一晩乾燥する。
1M溶液(5ml)、NaHCO3溶液(5ml)及びH2O(5ml)で抽出する。有機相をNa2SO4で脱水する。濾過後、混合物を真空下で濃縮し、残渣を0℃でエーテル中に沈殿させる。次いで、白色沈殿を濾過し、洗浄し、真空下で乾燥する。次いで、生成物をトルエン中の共沸混合物を用いて乾燥する。生成物を密封ボックス中に保存する。Mobt=0.4g,R=74%。
(C11),139.1(C12),155.8(C5’),167.5(COベンゾエート),168.7(COアセチル,4),170.0−174.0(C1’,−COO−スクシニック),205.4(C9)。
NaHCO3溶液(30ml)及び水(30ml)を用いて抽出する。その後、有機相をNa2SO4で脱水した後、濾過する。真空下で濃縮した後、残渣をMeOH(400ml)中に沈殿させる。濾過後、沈殿を真空下で一晩乾燥する。Wobt=1.5g,Y=75%。
上で得たコンジュゲート(VIII)(20mg)をアセトン(2ml)中に溶解させる(10mg/ml)。得られた溶液を脱イオン水(4ml)に撹拌しながら一滴ずつ添加する。アセトンを例えば回転蒸発器を用いて蒸発させる。こうして、5mg/mlのコンジュゲートの最終濃度を得る。
ュゲート(VIII’)の合成
100ml)で洗浄する。RTで一晩乾燥して、14gの白色粉末を得る。7.5gの固体をRTで一晩撹拌することによりメタノール(749ml)を用いて再精製し、濾過し、乾燥後、7.1gの白色粉末を得る。
1)PLA−PEG−Y−スクシニル−カバジタキセル(VIII’)(30mg)をアセトン(1.5ml)中に溶解させる。溶液を撹拌しながら(500rpmで20分間)WFI(3ml)中に一滴ずつ添加する。次いで、アセトンを回転蒸発器(300から45mbarで30分間)を用いて真空下37℃で蒸発させる。
スクシニル−ラロタキセルの製造
PLA−PEG−Y−スクシニル−ラロタキセル(30mg)をアセトン(1.5ml)中に溶解させる。溶液を撹拌しながら(500rpmで20分間)注射用水(WFI)(3ml)に一滴ずつ添加する。次いで、アセトンを回転蒸発器を用いて真空下37℃で蒸発させる。
平均直径(DLSを用いる)=48nm,PDI=0.17。
グルタリル−カバジタキセルの製造
PLA−PEG−Y−グルタリル−カバジタキセル(30mg)をアセトン(1.5ml)中に溶解させる。この溶液を撹拌(500rpmで20分間)しながらWFI(3ml)に一滴ずつ添加する。次いで、アセトンを回転蒸発器を用いて真空下37℃で蒸発させる。
平均直径(DLSを用いる)=60nm,PDI=0.21。
ジグリコリル−カバジタキセルの製造
.2g,0.0157mmol)、DCM(4ml)中のジグリコリル−カバジタキセル(32.3mg,2.2eq)、次いで粉末状活性化モレキュラーシーブ4A(100mg)を添加する。10分間撹拌した後、DMAP(4.4mg,2.3eq.)及びDIPC(4.3mg,2.2eq.)を添加する。懸濁液を35℃で24時間撹拌した後、濾過する(0.22ミクロン)。有機相を濃縮乾固し、抽出物をメタノール(40ml)及びジクロロメタン(2滴)で処理する。懸濁液をRTで2時間撹拌し、次いで濾過し、固体を減圧下RTで乾燥して、184mgの予想される化合物を得る。
PLA−PEG−Y−ジグリコリル−カバジタキセル(30mg)をアセトン(1.5ml)中に溶解させる。溶液を撹拌(500rpmで20分間)しながらWFI(3ml)に一滴ずつ添加する。次いで、アセトンを回転蒸発器を用いて真空下(30分間で300mbarから45mbarに)37℃で蒸発させる。
平均直径(DLSを用いる)=52nm,PDI=0.18。
3つのカバジタキセルコンジュゲートナノ粒子製剤、すなわちPLA−PEG−Y−スクシニル−カバジタキセル、PEG−Y−グルタリル−カバジタキセル及びPLA−PEG−Y−ジグリコリル−カバジタキセルからの遊離カバジタキセルのインビトロ放出カイネティックスをSprague Dawleyラットから得た血漿(血漿中10mMの最終濃度まで500mM リン酸緩衝液を用いて予め緩衝した)において高速液体クロマトグラフィー(HPLC)技術を用いて評価した。血漿アリコートを収容しているバイアルに、標準カバジタキセルまたはカバジタキセルコンジュゲートナノ粒子製剤(1mg/mL)を800μLの最終容量に達するようにマイクロピペットを用いて添加した。次いで、バイアルを撹拌装置(撹拌速度250rpm)上に37℃で置いた。サンプル分析を0時間目、1時間目、2時間目、4時間目、16時間目及び24時間目に実施した。
カバジタキセルを抽出した。次いで、内容物を10,000rpmで10分間遠心にかけ、透明な上清を集め、HPLCを用いて定量した。
カラム:150mm Zorbax SBフェニル 3.5μm
流束:1mL 分;カラム温度は30℃であった。
230nm(滴定のために使用した原理)及び210nmでの紫外(UV)二重検出モード
無勾配移動相:アセトニトリル 60%/水 40%/トリフルオロ酢酸 0.006%カバジタキセルの保持時間=4.1分。
Claims (4)
- 式(III):
−PLAはポリ乳酸であり;
−(mPEG)m基は、式:
−nはポリ乳酸断片の平均分子量であり、1000から50000(Daで表示)の範囲であり;
−Xは水素原子、または場合によりハロゲン原子、OR、CN、CF3、NRR'及びCOOR基から選択される1個以上の置換基で置換されているアルキル基であり、R及びR
'は同一または相互に異なっており、水素原子またはアルキル基である、
化合物。 - 段階2を前駆体3,6−ジメチル−[1,4]−ジオキサン−2,5−ジオンを用いる開環重合(ROP)により実施する、請求項2または3に記載の方法。
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FR1059561A FR2967581B1 (fr) | 2010-11-19 | 2010-11-19 | Conjugues polymeriques de principes actifs, leur procede de preparation et leurs intermediaires polymeriques |
FR1059561 | 2010-11-19 |
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US (1) | US9278137B2 (ja) |
EP (1) | EP2640422B1 (ja) |
JP (2) | JP6013354B2 (ja) |
AR (1) | AR084728A1 (ja) |
CY (1) | CY1119115T1 (ja) |
DK (1) | DK2640422T3 (ja) |
ES (1) | ES2625173T3 (ja) |
FR (1) | FR2967581B1 (ja) |
HR (1) | HRP20170691T1 (ja) |
HU (1) | HUE032590T2 (ja) |
LT (1) | LT2640422T (ja) |
PL (1) | PL2640422T3 (ja) |
PT (1) | PT2640422T (ja) |
RS (1) | RS56021B1 (ja) |
SI (1) | SI2640422T1 (ja) |
TW (1) | TW201302225A (ja) |
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WO2014015422A1 (en) * | 2012-07-27 | 2014-01-30 | Ontario Institute For Cancer Research | Cellulose-based nanoparticles for drug delivery |
JP6118914B2 (ja) * | 2012-12-28 | 2017-04-19 | ターベダ セラピューティクス インコーポレイテッドTarveda Therapeutics,Inc. | 放出制御型の固体ポリマーナノ粒子 |
ME02860B (me) | 2013-09-16 | 2018-04-20 | Astrazeneca Ab | Terapeutske polimerne nanočestice i postupci njihove pripreme i primene |
US10548881B2 (en) | 2016-02-23 | 2020-02-04 | Tarveda Therapeutics, Inc. | HSP90 targeted conjugates and particles and formulations thereof |
EP3823961A4 (en) * | 2018-07-19 | 2022-06-08 | Starpharma Pty Limited | THERAPEUTIC DENDRIMER |
CN110974972B (zh) * | 2019-12-03 | 2023-01-20 | 沈阳药科大学 | 难溶性药物的弱酸性衍生物及其脂质体制剂 |
CN113933441A (zh) * | 2021-09-30 | 2022-01-14 | 无锡紫杉药业有限公司 | 一种卡巴他赛及其中间体的测定方法 |
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CZ2006207A3 (cs) * | 2006-03-28 | 2008-01-16 | Zentiva, A. S. | Micelární nosiče léčiv s protinádorovou aktivitou |
CN101701068B (zh) * | 2009-10-30 | 2011-09-21 | 北京化工大学 | 一种pH响应性的Y型药物输送材料及其制备方法 |
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Publication number | Publication date |
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FR2967581A1 (fr) | 2012-05-25 |
LT2640422T (lt) | 2017-06-26 |
PT2640422T (pt) | 2017-05-23 |
HRP20170691T1 (hr) | 2018-05-18 |
HUE032590T2 (en) | 2017-10-30 |
CY1119115T1 (el) | 2018-02-14 |
RS56021B1 (sr) | 2017-09-29 |
WO2012066117A1 (en) | 2012-05-24 |
FR2967581B1 (fr) | 2012-12-28 |
DK2640422T3 (en) | 2017-05-22 |
JP2013542972A (ja) | 2013-11-28 |
SI2640422T1 (sl) | 2017-10-30 |
US9278137B2 (en) | 2016-03-08 |
EP2640422A1 (en) | 2013-09-25 |
AR084728A1 (es) | 2013-06-05 |
US20130243719A1 (en) | 2013-09-19 |
EP2640422B1 (en) | 2017-03-01 |
ES2625173T3 (es) | 2017-07-18 |
JP6013354B2 (ja) | 2016-10-25 |
UY33741A (es) | 2012-03-30 |
TW201302225A (zh) | 2013-01-16 |
PL2640422T3 (pl) | 2017-09-29 |
JP2016172858A (ja) | 2016-09-29 |
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