JP5727236B2 - 抗がん製剤 - Google Patents
抗がん製剤 Download PDFInfo
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- JP5727236B2 JP5727236B2 JP2011000720A JP2011000720A JP5727236B2 JP 5727236 B2 JP5727236 B2 JP 5727236B2 JP 2011000720 A JP2011000720 A JP 2011000720A JP 2011000720 A JP2011000720 A JP 2011000720A JP 5727236 B2 JP5727236 B2 JP 5727236B2
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- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Description
本特許出願は、2010年1月5日出願の、米国仮特許出願61/292,311号の優先権を主張し、これらの出願の内容は参照により本明細書に引用される。
n−ブチリデンフタリド(n-Butylidenephthalide)(Bdph)は、アンゼリカ・シネンシス(Angelica sinensis)から分離された化学化合物である。当該化合物は、たとえば、多形性膠芽腫(gliobastoma multiforme)および乳がん(breast cancer)のようなさまざまな腫瘍を治療するのに用いられうる。たとえば、Tsai et al., Clin. Cancer Res. 2005, 11(9):3475−3484、およびTsai, et al., J Neurochem. 2006, 99(4):1251−62を参照。しかしながら、その使用において、効果的ながん治療のためには、n−ブチリデンフタリドをがんの部位に選択的および持続的に運搬することが重要な意味を有する。このことは、血液脳関門(blood brain barrier)のために薬剤が疾患部位に到達するのが困難な脳腫瘍を治療するのに特に重要なことである。薬剤の運搬に効果的な方法を開発する必要があった。
本発明は、n−ブチリデンフタリド、特に、Z型n−ブチリデンフタリド(すなわち、(Z)−n−ブチリデンフタリド、z−ブチリデンフタリドおよびz−Bdph)が、E型n−ブチリデンフタリド(すなわち、(E)−n−ブチリデンフタリド、e−ブチリデンフタリドおよびe−Bdph)よりも、30日以上の長い期間を通じて放出され、抗腫瘍効果を有する製剤の発見に基づいている。
本発明のひとつの態様は、n−ブチリデンフタリド、特にそのz型、z−ブチリデンフタリド、および重合体を含む製剤に関する。該製剤は、多形性膠芽腫(glioblastoma multiforme)のような腫瘍の成長を抑制するのに用いることができる。
SA単量体を、2回アルコールから結晶化させた。2.7gのSA単量体を60mLの無水酢酸中で、30分間135〜140℃、真空下(10−4トール(torr))で還流した。未反応の無水酢酸を除去した。SAプレポリマー(SA prepolymer)を、真空下60℃で乾燥し、その後乾燥トルエン(dry toluene)に溶解した。乾燥エチルエーテルおよび石油エーテルの1:1(v/v)混合物に、この溶液を体積比1:10で加え、一晩静置し、SAプレポリマー(10:1 v/v)を析出させた。乾燥エチルエーテルおよび石油エーテルを除去した後、SAプレポリマーを真空下で乾燥させた。
z−Bdph−p(CPP−SA)ディスクを、0.1mLの0.1Mリン酸−緩衝生理食塩水(pH7.4)および1.0mLのn−オクタノールの入ったシンチレーションバイアル中に置き、37℃でインキュベーションした。溶液は、さまざまな時間において、新しい緩衝液に置き換えた。310nmの波長での吸収を、Weingart et al.,Int. J. Cancer. 1995,62(5):605−9に記載のように、分光光度計を用いて測定し、緩衝液中のz−Bdphの濃度を決定した。z−Bdphの持続的な放出が確認された。
RG2ラット多形性膠芽腫(glioblastoma multiforme)(GBM)細胞におけるp(CPP−SA)−10%z−Bdphの成長抑制効果(the growth inhibitory effects)の分析測定を行った。RG2細胞を、10%Bdph−ウエハ(wafer)で24時間処理した。細胞生存率(Cell viability)を、MTT分析により測定した。p(CPP−SA)−10%z−Bdphの成長抑制効果は、コントロールと比較すると、50%であることがわかった。さらに、GBM細胞の形態は徐々に変化し、そして処理後には培養皿の下部から細胞の分離が観測された。未処理の細胞と比較すると、分離したGBM細胞のほとんどは、p(CPP−SA)−10%z−Bdph処理後にアポトーシス(apoptotic)した。
オリゴデオキシヌクレオチドのマクロアレイ分析(oligodeoxynucleotide-based microarray analysis)の結果を確認するために、z−Bdph処理したRG2細胞中のオーファン受容体(orphan receptors)NOR−1、Nurr1、およびNur77の発現をRT−PCRにより調べた。
National Laboratory Animal Center(台北、台湾)から、オスのF344ラット(230−260g)およびオスのFoxn1 nu/nuマウス(10−12週)を入手した。すべての手順を、ナショナルTau Hwaユニバーシティ(ホァーリュン(Hualien)、台湾)およびチャイナメディカルユニバーシティホスピタル(台中(Taichung)、台湾)のLaboratory Animal Centerの標準作業手順に従って行った。RG2細胞およびDBTRG−05MG細胞を動物実験に用いて、p(CPP−SA)−3%または10%z−Bdph製剤およびp(CPP−SA)−3%BCNUの抗腫瘍活性(anti-tumor activities)を測定した。
もとの注射部位から少なくとも1.5cmを除去した。
F344ラットの後部脇腹領域に、RG2細胞(5×106)を皮下移植した。RG2細胞移植の5日後、ラットに、p(CPP−SA)−3%z−Bdph、p(CPP−SA)−10%z−Bdph、p(CPP−SA)のみ、またはp(CPP−SA)−3%BCNUを皮下に処理した。p(CPP−SA)−3%z−Bdph処理群、p(CPP−SA)−3%BCNU処理群、およびp(CPP−SA)処理群に比べて、p(CPP−SA)−10%z−Bdph処理群において、大きな腫瘍成長抑制が観測された(p<0.005)。
Foxnlヌードマウスに、ヒトDBTRG−05MG細胞(2×106)を接種させ、5日目にp(CPP−SA)−z−Bdph(0%、3%、10%)を移植した。3%および10%のz−Bdph−ウエハ処理群の腫瘍成長の著しい抑制が観測された。39日目の腫瘍サイズの平均値は、コントロール群 1098.46±170.11、p(CPP−SA)−3%z−Bdph処理群 605.8±98.8mm3、p(CPP−SA)−10%z−Bdph処理群 504.4±38.9mm3であった(p<0.05)。
DBTRG−05MG細胞の浸潤を、バイオコート腫瘍浸潤チャンバーシステム(BioCoat matrigel invasion chamber system)(BD Bioscience,Bedford,MA)を用いて測定した。BDマトリゲルマトリックス(BD matrigel Matrix)は、8μmの孔径を有するポリエチレンテレフタレート(PET)メンブレン上、ラミニン、コラーゲンIV、ニドジェン/エンタクチン(nidogen/entrctin)、およびプロテオグリカンから構成される。In Vitroの転移分析では、ファルコンカルチャーインサート(Falcon culture insert)(BD Bioscience)上の低い細孔密度(pore density)のPETトラックエッチドメンブレン(track-etched membrane)が適用された。メンブレンを、マトリゲルチャンバーまたはファルコンカルチャーインサートの上部と下部ウエルの間に置いた。まず最初に、10%ウシ胎仔血清(fetal bovine serum)を含むPRMI1640中に細胞を再懸濁し、チャンバーの上部ウエル中にシードした(1ウエルにつき細胞50,000)。24時間37℃でインキュベートした後、メンブレンを浸潤または転移した細胞を、Liu染色(Handsel Technologies,Inc.,台北、台湾)で染色し、顕微鏡下でカウントした。それぞれの実験は、3回繰り返した。
悪性の脳腫瘍をz−Bdphが抑制するメカニズムを解明するため、逆転写ポリメラーゼ連鎖反応(RT−PCR)を用いて、GBM細胞の遺伝子発現プロファイル上のz−Bdphの効果を調べた。Axlレセプターチロシンキナーゼ(RTK)のmRNA発現が、z−Bdphの存在下で下方制御されたことがわかった。
他の実施形態
本明細書に開示された全ての特徴は、任意の組み合わせで組み合わせられうる。本明細書に開示のそれぞれの特徴は、同一の、均等な、または類似の目的を達成する他の特徴により置換されうる。よって、特記しない限り、開示されたそれぞれの特徴は、広範な一連の均等なまたは類似の特徴の一例に過ぎない。
Claims (14)
- z−ブチリデンフタリド、およびz−ブチリデンフタリドと混合された重合体を含み、前記重合体が、乳酸・グリコール酸共重合体、キトサン、コラーゲン、ポリ無水物、およびこれらの混合物からなる群より選択される、製剤。
- 前記ポリ無水物が、ビス(p−カルボキシフェノキシ)プロパン、ビス(p−カルボキシフェノキシ)ブタン、ビス(p−カルボキシフェノキシ)ペンタン、ビス(p−カルボキシフェノキシ)ヘプタン、ビス(p−カルボキシフェノキシ)ヘキサン、ビス(p−カルボキシフェノキシ)オクタン、イソフタル酸、1,4−フェニレンジプロピオン酸、ドデカンジオン酸、シュウ酸、マロン酸、コハク酸、グルタル酸、アジピン酸、ピメリン酸、スベリン酸、アゼライン酸、セバシン酸、フタル酸、イソフタル酸、テレフタル酸、またはこれらの混合物から調製される、請求項1に記載の製剤。
- 前記ポリ無水物が、ビス(p−カルボキシフェノキシ)プロパン、ビス(p−カルボキシフェノキシ)ヘキサン、イソフタル酸、1,4−フェニレンジプロピオン酸、ドデカンジオン酸、セバシン酸、またはこれらの混合物から調製される、請求項2に記載の製剤。
- 前記ポリ無水物が、ビス(p−カルボキシフェノキシ)プロパンおよびセバシン酸の混合物から調製される、請求項3に記載の製剤。
- ビス(p−カルボキシフェノキシ)プロパンおよびセバシン酸の比が、1:2〜1:10である、請求項4に記載の製剤。
- ビス(p−カルボキシフェノキシ)プロパンおよびセバシン酸の比が、1:4〜1:5である、請求項5に記載の製剤。
- 製剤中のz−ブチリデンフタリドの重量パーセントが3%〜20%である、請求項1〜6のいずれか1項に記載の製剤。
- 製剤中のz−ブチリデンフタリドの重量パーセントが約10%である、請求項7に記載の製剤。
- 粉体、ウエハ、シート、棒、マイクロスフィア、ナノスフィア、ペースト、または糊の形態である、請求項1〜8のいずれか1項に記載の製剤。
- 腫瘍の治療のために使用される、請求項1〜9のいずれか1項に記載の製剤。
- 前記腫瘍が、多形性膠芽腫、肺がん、肝細胞がん、結腸がん、黒色腫、乳がん、神経芽
細胞腫、奇形腫またはヒト白血病である、請求項10に記載の製剤。 - 患者の皮下に移植され、間質に移植され、または頭蓋内に移植される、請求項10または11に記載の製剤。
- 前記腫瘍が、多形性膠芽腫である、請求項11または12に記載の製剤。
- z−ブチリデンフタリドが、Axlが媒介する腫瘍細胞の増殖、転移または浸潤を抑制する、請求項13に記載の製剤。
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US7496945B2 (en) | 2001-06-29 | 2009-02-24 | Cisco Technology, Inc. | Interactive program guide for bidirectional services |
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US8927601B2 (en) | 2011-12-20 | 2015-01-06 | National Dong Hwa University | Uses of N-butylidenephthalide in treating a liver injury and improving liver function |
TWI472519B (zh) * | 2011-12-20 | 2015-02-11 | Nat Univ Dong Hwa | 含正-亞丁基苯酞之醫藥組成物用於治療肝損傷及改善肝功能 |
TWI522099B (zh) * | 2014-06-04 | 2016-02-21 | 中國醫藥大學 | 治療胰臟癌之醫藥配方及其應用 |
TWI511727B (zh) | 2014-07-02 | 2015-12-11 | Everfront Biotech Inc | 苯酞化合物之應用 |
NZ728386A (en) * | 2014-07-04 | 2018-02-23 | Everfront Biotech Inc | Use of phthalide compound |
EP3175851B1 (en) * | 2014-07-28 | 2021-08-18 | Everfront Biotech Inc. | Use of butenylphthalide, usage method thereof and method for preparing same into pharmaceutical composition |
CN105311014A (zh) * | 2014-07-28 | 2016-02-10 | 李德财 | 丁烯基苯酞的用途及将其制备为医药组合物的方法 |
US10688128B2 (en) * | 2016-05-23 | 2020-06-23 | Everfront Biotech Inc. | Use of Z-butylidenephthalide in activating autoimmune system |
CN113425707B (zh) * | 2021-07-30 | 2022-12-30 | 青岛大学附属医院 | 壬二酸预防蒽环类抗肿瘤药物心肌毒性的应用 |
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US7138105B2 (en) | 2002-02-27 | 2006-11-21 | Pharmain | Compositions for delivery of therapeutics and other materials, and methods of making and using the same |
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