JP2016172858A - 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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- JP2016172858A JP2016172858A JP2016080318A JP2016080318A JP2016172858A JP 2016172858 A JP2016172858 A JP 2016172858A JP 2016080318 A JP2016080318 A JP 2016080318A JP 2016080318 A JP2016080318 A JP 2016080318A JP 2016172858 A JP2016172858 A JP 2016172858A
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- 125000004036 acetal group Chemical group 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000000149 argon plasma sintering Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000006065 biodegradation reaction Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- BBWBEZAMXFGUGK-UHFFFAOYSA-N bis(dodecylsulfanyl)-methylarsane Chemical compound CCCCCCCCCCCCS[As](C)SCCCCCCCCCCCC BBWBEZAMXFGUGK-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000000451 chemical ionisation Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 150000002009 diols Chemical group 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229940072106 hydroxystearate Drugs 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000569 multi-angle light scattering Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-O n,n-dimethylpyridin-1-ium-4-amine Chemical compound CN(C)C1=CC=[NH+]C=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-O 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000007694 nephrotoxicity Effects 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000000962 organic group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 2
- 229920001553 poly(ethylene glycol)-block-polylactide methyl ether Polymers 0.000 description 2
- 239000008389 polyethoxylated castor oil Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001226 reprecipitation Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000013269 sustained drug release Methods 0.000 description 2
- 230000001839 systemic circulation Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- FGGUAEKPLDMWSF-HMHFYOQSSA-N chembl2376821 Chemical compound O([C@@H]1[C@@H]2[C@@H]3O[C@]3(CO)[C@@H](O)[C@@]3(O)[C@H]([C@]2([C@H](C)C[C@@]1(O1)C(C)=C)O2)C[C@@H]([C@@H]3O)C)C21C1=CC=CC=C1 FGGUAEKPLDMWSF-HMHFYOQSSA-N 0.000 description 1
Classifications
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- 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
- 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
- A61K47/60—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 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
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Abstract
Description
−ポリエチレングリコール−ポリラクチド(MPEG−PLA)のコンジュゲートを提供している。しかしながら、PLAの末端に結合している活性成分がこうして形成されたミセルの疎水性領域に捕捉されており、実際殆ど接近不可能である。
−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150
00(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。
カップリングにより得られ得る。
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。
の分布を表す。
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。
EG2000と称する)(10g,5mmol)及び保護されているビス−MPA(I)(1.35g,6.1mmol)を250mlのシュレンク容器において無水DCM(45ml)中に溶解させる。その後、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDCI)(0.96g,5mmol)及びp−トルエンスルホン酸4−(ジメチルアミノ)−ピリジニウム(DPTS)(0.6g,2mmol)を媒体に添加する。反応媒体をアルゴン下40℃で48時間撹拌する。その後、反応媒体を1M HCl溶液(20ml)、10% NaHCO3溶液(20ml)及びH2O(20ml)で抽出する。
(C5),58.8(C1),63.2(C3),67.1(C7),68.7(C2’),70.4(C2),71.8(C2”’),72.6(C2”),175.5(C4)。
に溶解させた後、0℃でエーテル(800ml)から沈殿させる。白色沈殿を濾別した後、真空下で一晩乾燥する。Wobt=2.14g,Y=55%。
l)を無水DCM(5ml)中に溶解させる。次いで、トリエチルアミン(TEA)(KOHで蒸留)(0.2g,2.01mmol)を添加し、トリス−イソプロピルクロロシラン(TIPSCl)(0.40g,2mmol)を0℃で一滴ずつ添加する。反応混合物をアルゴン下40℃で撹拌する。24時間後、形成された塩を濾過し、有機相をHCl
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%。
,14a&14b),2.34(s,3H,−CH3アセチル,4),2.65(m,5H,−CH2スクシニックa,a’&6b),3.28(s,3H,−OCH3,7),3.44(s,3H,−OCH3,10),3.80(d,1H,3,J=7.5Hz),3.84(dd,1H,7,J=6.5及び10.5Hz),4.16(d,1H,20a,J=8.5Hz),4.28(d,1H,20b,J=8.5Hz),4.80(s,1H,10),4.95(d,1H,5,J=10Hz),5.28−5.44(br,2H,2’/4’),5.61(d,1H,2,J=7.5Hz),6.19(b,1H,13),7.31,7.38,7.47,7.59,(m,9H,ArH),8.10(d,2H,Hオルトベンゾエート)。
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%。
リンカー−(CH2)−のシグナルのシフト:28.13及び26.71ppm。
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。
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。
t,J=7.9Hz,2H);7.50(t,J=7.9Hz,2H);7.61(t,J=7.9Hz,1H);8.11(d,J=7.7Hz,2H)。
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
(33mg,0.27mmol)を添加する。溶液を30℃に一晩加熱し、次いで水(47ml)で2回洗浄する。有機溶液をMgSO4で脱水した後、溶液を減圧下40℃で濃縮乾固する。乾燥抽出物を3容量のジイソプロピルエーテルで処理し、懸濁液を2時間撹拌し、濾過し、固体を2容量のジイソプロピルエーテルで2回洗浄する。減圧下40℃で乾燥後、2.28gの白色粉末を得る。
1H);7.30(m,3H);7.39(t,J=7.7Hz,2H);7.51(t,J=7.7Hz,2H);7.61(t,J=7.7Hz,1H);8.18(d,J=7.7Hz,2H)。
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
2H);7.74(t,J=7.7Hz,1H);7.85(d 大きい,J=9.1Hz,1H);7.98(d,J=7.7Hz,2H);12.13(非常に広幅s,1H)。
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
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。
バジタキセルの<1%)のスクシニル−カバジタキセルしか製剤から放出されなかったことを示した。結局、薬物放出の順序は次の通りであった:PLA−PEG−Y−ジグリコリル−カバジタキセル>PLA−PEG−Y−グルタリル−カバジタキセル>PLA−PEG−Y−スクシニル−カバジタキセルナノ粒子。これらの結果は、異なるリンカーを有するカバジタキセルコンジュゲートによりインビトロ放出プロフィールが異なることを示している。
−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)
- 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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GB9721069D0 (en) | 1997-10-03 | 1997-12-03 | Pharmacia & Upjohn Spa | Polymeric derivatives of camptothecin |
WO2011119995A2 (en) * | 2010-03-26 | 2011-09-29 | Cerulean Pharma Inc. | Formulations and methods of use |
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WO2007110003A2 (en) * | 2006-03-28 | 2007-10-04 | Zentiva, A.S. | Micellar carriers for drugs with anti-cancer activity |
CN101701068A (zh) * | 2009-10-30 | 2010-05-05 | 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 |
CN103408710A (zh) * | 2013-06-19 | 2013-11-27 | 北京化工大学 | 一种生物可降解及糖响应性的y型高分子药物输送材料及制备 |
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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 |
JP6165920B2 (ja) | 2017-07-19 |
TW201302225A (zh) | 2013-01-16 |
PL2640422T3 (pl) | 2017-09-29 |
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