TW200815053A - Nanoparticles comprising a PDGF receptor tyrosine kinase inhibitor - Google Patents
Nanoparticles comprising a PDGF receptor tyrosine kinase inhibitor Download PDFInfo
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- TW200815053A TW200815053A TW096110152A TW96110152A TW200815053A TW 200815053 A TW200815053 A TW 200815053A TW 096110152 A TW096110152 A TW 096110152A TW 96110152 A TW96110152 A TW 96110152A TW 200815053 A TW200815053 A TW 200815053A
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- nanoparticle
- nanoparticles
- kinase inhibitor
- tyrosine kinase
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Description
200815053 九、發明說明： 【發明所屬之技術領域】 本發明係關於包含血小板衍生生長因子（PDGF)受體酪胺 i激酶抑制劑的奈米粒子，尤其包含呈游離形式或呈醫藥 产 學上可接受之鹽形式的式1之”-苯基-2-嘧啶-胺衍生物的奈 • 米粒子，其中符號及取代基具有下文中所給出之含義；關 於諸如伊馬替尼之PDGF受體酪胺酸激酶抑制劑經生物可 吸收聚合奈米粒子的細胞内輸送；該等奈米粒子於製造供 # ’冶療血管平滑肌細胞生長疾病之醫藥組合物中的用途；關 於治療罹患金管平滑肌細胞生長疾病之包括人類之溫血動 物的方法，關於製備該等奈米粒子的方法；關於包含該等 示米粒子的w藥組合物，且係關於倂有該等奈米粒子以預 防及治療A管平滑肌細胞纟長疾㈣藥物輸送系統。 【先前技術】 血管平滑肌細胞（SMC)及單核細胞表現之？1)(}?在實驗動 # 物之再狹窄及動脈粥樣硬化血管疾病中起關鍵作用 (Myilarmemi Cardiovasc Drugs Ther. Ϊ999; 13:159-68) 〇 限制或阻塞冠狀或周邊血流之動脈粥樣硬化病變為包括冠 - 心病及中風之缺血性疾病相關發病及死亡的主要起因。已 • 知諸多有機化合物抑制PDGF受體之酪胺酸激酶活性。特 定而言，已知一種式1(見下文）之冰苯基嘧啶_胺衍生物 的甲磺酉变鹽，伊馬替A甲石黃酸鹽⑹“獸復）能抑制該 PDGF受體㈣酸激酶活性。鑒於此抑制效果，伊馬替尼 甲磺酸鹽當前處於惡性神經膠質瘤臨床試驗的評估中 119075.doc 200815053 (Radford，I· R·，Curr. Opin· Investig. Drugs，3: 492-499 2002)。然而’在J Am Coll Cardiol· 2005; 46:1999-2003 中 D· Zohlnhofer等人所報導之臨床研究中未觀察到全身投與 伊馬替尼抗紫再狹窄的有益效果。 ，現意外地發現藉由奈米粒子技術細胞内輸送PDGF受體 酿胺酸激酶抑制劑為諸如再狹窄、動脈粥樣硬化血管疾病 及原發性肺動脈高壓之血管平滑肌細胞生長疾病的有利治 療策略。 •【發明内容】 因此，本發明係關於包含PDGF受體酪胺酸激酶抑制劑 的奈米粒子’尤其包含呈游離形式或呈醫藥學上可接受之 鹽形式的式I之N-苯基_2_嘧啶·胺衍生物的奈米粒子，其中 符號及取代基具有下文中所給出之含義(下文中稱為本發 明之奈米粒子）。 在車又仏具施例中，本發明係關於包含式][之N-苯基_2_ • %徙-胺何生物或具有至少一個成鹽基團之該化合物之鹽 的奈米粒子， &
其中 R1為4 -σ比。秦基；1 _审| 土 - Η-吡咯基；胺基取代或胺基·低碳 119075.doc 200815053 烧基取代之苯基，其中該胺基在各種情況下呈游離、烧 化或醯化形式；在五員環碳原子處鍵結之m、丨哚基: 1H-味也基；或在環碳原子處鍵結之未經取代或低碳烧 基取代之吼啶基且其未經取代或在氮原子處經氧取代； R2與R3各自彼此獨立地為氫或低碳烷基； 基團I、R5、Re、R?與Rs中之一或兩者各自為硝基、氟基 取代之低石反烧氧基或式Π之基團 -n(r9)-c(哪⑺n-Rl0 (II)， 其中 R9為氫或低碳烷基， X為側氧基、硫基、亞胺基、N_低碳烷基_亞胺基、肟基 或0-低碳烷基-肟基， Y為氧或基團NH， η為0或1且
Rio為具有至少5個碳原子之脂族基團，或芳族、芳族_脂 族、環脂族、環脂族-脂族、雜環或雜環_脂族基團， 且其餘基團R4、R5、R0、R7及R8各自彼此獨立地為氫， 未經取代或經游離或烷化胺基、哌嗪基、哌σ定基、吡咯淀 基或經嗎啉基取代之低碳烷基，或低碳烷醯基，三氟甲 基，游離、醚化或酯化羥基，游離、烷化或醯化胺基，或 游離或酯化羧基。 1-甲基-ΙΗ-吼洛基較佳為1-甲基_ iH-吼嘻-2·基或1-曱基- 1Η-口比口各-3-基。 其中胺基在各種情況下呈游離、烷化或醯化形式之胺基 119075.doc 200815053 取代或胺基-低碳烷基取代之苯基Rl為在任何所需位置 (鄰、間或對）經取代之苯基，其中烷化胺基較佳為單低碳 烷基胺基或二低碳烧基胺基，例如二甲基胺基，且胺基_ 低碳烧基之低碳烷基部分較佳為直鏈(：：1-〇：3烷基，諸如尤 其曱基或乙基。 在五員環之碳原子處鍵結之1H-吲哚基為1H-吲哚-2-基 或1Η -ϋ引ϋ朵-3 -基。 在環碳原子處鍵結之未經取代或低碳烷基取代之吡啶基 為低碳烧基取代或較佳未經取代之2-啦σ定基、4-«比咬基或 較佳3-u比啶基，例如3_吡啶基、2-甲基·3-吡啶基或4-甲基-3-啦唆基。在氮原子處經氧取代之吡啶基為衍生自吡啶Ν_ 氧化物之基團，亦即1SM申氧吡啶基。 氟基取代之低碳烷氧基為具有至少一個，但較佳若干個 氟基取代基之低碳烷氧基，尤其三氟曱氧基或込^孓四 氣-乙氧基。 φ 當Χ為側氧基、硫基、亞胺基、Ν-低碳烷基-亞胺基、肟 基或0-低碳烷基-肟基時，基團C=X按以上次序分別為基 團 〇0、C=S、ON-H、ON-低碳烷基、C=N-OH或 C=N-0-低碳烷基。χ較佳為側氧基。 η較佳為〇，亦即基團γ不存在。 Υ若存在則較佳為基團ΝΗ。 此正文範圍内之術語"低碳"表示具有至多且包括7個， 較4土至多且包括4個碳原子的基團。 低碳烧基R〗、R2、尺3及尺9較佳為曱基或乙基。 119075.doc 200815053 八有至:> 5個;ε反原子的脂族基團r〗〇較佳具有不多於μ個 厌原子通_不多於丨〇個碳原子，且為此經取代或較佳未 經取代之脂族煙|，亦即此經取代或較佳未經取代之块 基、烯基或較佳烷基，諸如C5_C7烷基，例如正戊基。茅 奴基團R10具有至多2〇個碳原子且未經取代或經取代，例 如在各種情況下未經取代或經取代之萘基，諸如尤其2•蔡 基，2較佳苯基，取代基較佳選自氰基；未經取代或羥 基、胺基或4-甲基-哌嗪基取代之低碳烷基，諸如尤其甲 基^三氟f基，游離、喊化或醋化經基，游離、院化或酿 ，胺基及游離或酯化羧基。在芳族·脂族基團I。中，芳族 邛刀如上所定義且脂族部分較佳為低碳烷基，諸如尤其經 取代或較佳未經取代之Cl_C^基，例如f基。環脂族基 ^Rl。具有尤其至多3G個’更尤其至多20個，且最尤其至 多個碳原子’為單環或多環且經取代或較佳未經取代， 例如該環院基，尤其該5員或6員環烧基，諸如較佳環己 基。在環脂族-脂族基團‘中，環脂族部分如上所定義且 脂族部分較佳為低碳烷基，諸如尤其經取代或較佳未經取 代之Cl-C2烷基。雜環基團Ri〇含有尤其至多2〇個碳原子且 k佳為具有5個或6個環成員及丨至3個較佳選自氮、氧及硫 之雜原子的飽和或不飽和單環基團，尤其例如噻吩基或 °比咬基、3·㈣基W定基，或其中例如—或㈣苯基 團增添（稠合）至所述單環基團上的雙環或三環基團。在雜 ^脂族基團R1G中’雜環部分如上所^義且脂族部分較佳 為低碳烷基，諸如尤其經取代或較佳未經取代之Cl_C2烷 H9075.doc 200815053 基。 · 醚化說基較佳為低碳烧氧基。酯化經基較佳為經諸如低 礙烧酸之有機羧酸或諸如例如低碳烷醯基氧基之氫鹵酸之 無機酸或諸如碘、溴或尤其氟或氯之鹵素酯化的羥基。 烧化胺基例如為諸如曱基胺基之低碳烷基胺基，或諸如 一甲基胺基之二低碳烧基胺基。醯化胺基例如為低碳烧酿 基胺基或笨甲醯基胺基。 醋化魏基例如為諸如甲氧基羰基之低碳烷氧羰基。 經取代之苯基可具有至多5個取代基，諸如氟，但尤其 在相對大取代基之情況下通常經僅i至3個取代基取代。可 特別提及之經取代苯基之實例為4_氯_苯基、五氟苯基、2_ 羧基-苯基、2-甲氧基-苯基、4-氟-苯基、4-氰基-苯基及4-曱基-苯基。 式I化β物中之成鹽基團為具有驗性或酸性之基團。具 有至少一個驗性基團（例如游離胺基、吡嗪基或吡啶基）之 化合物可與以下各酸形成酸加成鹽：例如無機酸，諸如氫 氣酸、硫酸或磷酸；或合適有機羧酸或磺酸，例如脂族單 魏fee或一缓酸’諸如三氟乙酸、乙酸、丙酸、經基乙酸、 丁二酸、順丁烯二酸、反丁烯二酸、羥基順丁烯二酸、經 基丁二酸、酒石酸、擰檬酸或草酸；或胺基酸，諸如精胺 酸或離胺酸；芳族羧酸，諸如苯甲酸、2-苯氧基-苯甲酸、 2-乙醯氧基-苯甲酸、水揚酸、‘胺基水楊酸；芳族_脂族 叛酸’諸如爲桃酸或肉桂酸；雜芳族羧酸，諸如菸鹼酸或 異於鹼酸；脂族磺酸，諸如甲烷磺酸、乙烷磺酸或2-羥基 119075.doc 200815053 乙烧續酸m㈣酸，例如笨料、對甲料酸或蔡_2_ 石黃酸。當存在若干鹼性基團時，可形成單酸或多酸加成 在基團Rl0中具有例如游離羧基之酸性基團的式工化合物 可形成金屬鹽或銨鹽’諸如驗金屬或驗土金屬冑，例如納 鹽、鉀鹽、鎂鹽或鈣鹽；或與氨，或諸如例如三乙胺或三 (2-經乙基）.胺之第三單胺的合適有機胺，或例^n_乙基_
哌啶或N，N’-二甲基-哌嗪之雜環鹼的銨鹽。 較佳為包含式RN-苯基·2·嘧唆·胺：生物的奈米粒子， 其中 基團R4、R5、R6、R8中之_或兩者各自為硝基或式 II之基團，其中 R9為氫或低碳烷基， X為側氧基、硫基、亞胺基、义低碳烧基_亞胺基、將基 或Ο _低故烧基-將基， γ為氧或基團NH， η為0或1且
Rio為具有至少5個碳原子之脂族基團’或芳族、芳族-脂 族、環脂族、環脂族·脂族、雜環或雜環.脂族基團， 且其餘基團R4、R5、R6、及R8各自彼此獨立地為氫， 未經取代或經料W切基、料基ϋ基、料咬 基或L嗎琳基取代之低碳烧基’或低碳院醯基，三氣甲 基，游離、醚化或酿化經基，游離、烧化或醯化胺基，或 游離或酯化羧基， 119075.doc 200815053 且其餘取代基如上所定義。 車父佳為包含式I之N-苯基-2-嘧啶-胺衍生物的奈米粒子， 其中
Rl為在碳原子處鍵結之吡啶基， R2、R3、R5、R6&R8各自為氫， R4為低碳烧基， R7為式II之基團，其中 R9為氯， 為側氧基， η為〇且
Rio為4-甲基-旅嗓-甲基。 所有上述較佳為包含為STI571(亦稱為伊馬替尼或N-{5-[4-(4-甲基-旅嗪基甲基）_苯曱醯胺基]_2-曱基苯基}_4_(3_ 。比咬基）_2_嘧啶-胺})之式-苯基-2_嘧啶，衍生物的奈 米粒子。 極佳地，使用呈其單甲磺酸鹽形式的伊馬替尼。伊馬替 尼單曱磺酸鹽極易溶於水（在20。(：約100 g/1 〇〇 ml至i 5〇 g/100 ml)。因此，本發明進一步提供包含極易溶於水，尤 其在20°C具有介於約2.5 g/100 ml與約25 0 g/l〇〇 mi之間， 更佳介於約5 g/l〇〇 mi與約丨75 g/100 ml之間，最佳介於約 75 g/100 ml與約150 g/i〇〇 ml之間的水溶解度之pdgf受體 酪胺酸激酶抑制劑的本發明奈米粒子。 式I之N-苯基-2-嘧啶-胺衍生物一般且特定地揭示於美國 專利第US 5,521，184號及專利申請案WO 99/03854，尤其 119075.doc •12- 200815053 化合物請求項及工作實例之最終產物中。因此實例最終產 物及醫藥製劑之主題以引用此等公開案的方式併入本申請 案中。同樣包含其中揭示之相應立體異構體以及例如晶體 麦型之相應多晶形物。WO 03/066613中揭示式I之N-苯基· 2-嘧啶_胺衍生物之便利製備方法。 另外合適PDGF受體酪胺酸激酶抑制劑揭示於例如w〇 98/35958(尤其實例62化合物）及US 5,〇93,33〇中，在各種情 況下’尤其揭示於化合物請求項及工作實例之最終產物 中，其主因此以引用此等公開案的方式併入本申請案 中〇 表述”血管平滑肌細胞生長疾病”尤其係指再狹窄、動脈 粥樣硬化企管疾病及原發性肺動脈高壓。 如本文所用之術語”奈米粒子"係指平均直徑約2 · 5 nm至 約1000 nm、較佳5 nm至約500 nm、更佳25 nm至約75 nm 且最有利介於約40 urn與約50 nm之間的粒子。本發明尤其 係關於包含生物可降解聚酯之生物可吸收聚合奈米粒子。 ”生物可降解聚酯”係指較佳由選自由以下各物組成之群 的單體合成之任何生物可降解聚酯：D，L-丙交S旨、D-丙交 酯、L-丙交酯、D，L-乳酸、D·乳酸、L-乳酸、乙交自旨、經 基乙酸、E-己内|旨、E-經基己酸、丁内g旨、經基丁 酸、8-戊内酯、8-羥基戊酸、羥基丁酸、羥基丁二酸及其 共聚物。 如本文所用之術語’’PLGA"係指由各種比率之乳酸或丙 交酯（LA)及羥基己酸或乙交酯（GA)組成之共聚物。共聚物 119075.doc -13· 200815053 產生不同内部黏度及不同聚合物 可具有不同平均鏈長度 性質。 較仏生物可降解聚合奈米粒子為聚乙二醇（刚）改質之 聚丙父S旨-乙交醋共聚物（PLGA)奈米粒子。可例如藉由應 用例如揭示於實例中之球形結晶技術來獲得平均直徑50 nm 的該等奈米粒子。 如以:實财料’以生物可降解聚合奈綠子技術細
胞内輸送伊馬替尼有效抑制血管平滑肌增殖及血管平滑肌 細胞遷移。 在另一態樣中，本發明係關於併有本發明奈米粒子以預 防及治療血管平滑肌細胞生長錢㈣物輸送系統。 :多人患有由灌心臟及其他主要器官之4的進行性 P基所引起的循環疾病。此等人體内血管嚴重阻塞常導致 缺血性扣知、咼血壓、中風或心肌梗塞。限制或阻塞冠狀 或周邊血流之動脈粥樣硬化病變為包括冠心病及中風之缺 血性疾病相關發病及死亡的主要起因。為終止疾病進程且 預防〜肌或其他器官受損的更晚期病狀，使用諸如經皮經 管腔冠狀血管成形術（PCTA)、經皮經管腔血管成形術 (PTA)、粥樣斑切除術、旁路移植或其他類型血管移植程 序0 各種血管再形成程序後，視所用程序及動脈部位而定， 進行此治療的10-80%患者出現動脈粥樣硬化冠狀動脈再變 窄（例如再狹窄）。除打開動脈粥樣硬化所阻塞之動脈以 外，血管再形成亦損傷管壁内的内皮細胞及平滑肌細胞， 119075.doc -14- 200815053 由此引起血栓形成及發炎反應。諸如PDGF之細胞衍生生 長因子、浸潤巨噬細胞、白細胞或平滑肌細胞自身引起平 滑肌細胞的增殖及遷移反應。與局部增殖及遷移同時發 生’發炎細胞亦侵入血管損傷部位且可遷移至管壁之較深 層0 動脈粥樣硬化病灶内之細胞與培養基内之細胞均遷移、 增殖及/或分泌大量細胞外基質蛋白。增殖、遷移及細胞
外基貝合成繼續直至受損内皮層得以修復，此時内膜中之 增殖減慢。新形成之組織稱為新生血管内膜、内膜增厚或 再狹窄病變且通常導致管内腔變窄。進一步内腔變窄=因 導致進一步内膜增厚或增生的結構性重塑（例如血管重塑） 而發生。 --P ”丨L仁7Γ夕取尸；T謂”易損 斑塊"的動脈粥樣硬化病變。該等動脈粥樣硬化病灶或易 損斑塊易於破裂或潰爛，從而引起血栓且因此導致不^ 心絞痛、心肌梗塞或猝死。發炎動脈粥樣硬化斑塊可2 度記錄法偵測。 與金管通路裝置相關之併發症為許多病狀發病的主 因。例如血液透析患者之血管通路功能不良通常係 循環中外流狹窄引起（Sehwam s • J·寺人，Kidney lnt 36 707-71 1，1989)。血管通踗如關欢— · 0 ^ _發病㈣有晚期腎病住院 患者的約23%且耗費該等电奂夕★ ^ 1 Ιπ 丰㈣d Η Τ Τ Α 達所有住院治療費用的一 牛（Feldman H.I.，J. Am 'τ , S〇C*NePhr〇l. 7: 523-535,1996^0 此外’化療患者之血管通路功 卜良遇吊係由靜脈循環中 119075.doc 200815053 外流狹窄引起且導致將藥物投與癌症患者的能力減小。外 流狹窄常如此嚴重以致於需要介入。此外，全靜脈營養、、二 療⑽）患者之血管通路功能不良通常係由靜脈循環中外 流狹窄引起且導致護理此等患者的能力減小。迄今為止， 尚無任何用於預防或減弱伴隨至尤其為人類患者：哺乳動 物靜脈中插人或修復留置旁通管、瘺管或諸如大孔徑導管 ^導管發生的血管通路功能不良之有效藥物。患有㈣二 哀竭之患者的存活依賴於透析的最優恆常效能1此舉不 可達成（例如歸因於血管通路功能不良或衰竭），則其二致 快速臨床劣化且除非狀況得到補救，否則該等患者將死 亡。血液透析需要循環通路。血液透析血管通路的理相妒 =使得重複通路„，提供高血流速率，且伴有最^ 二正。目别，三種血管通路形式為自體動靜脈内痛 (# )、合成移植及中樞靜脈導管。移植最通常包含聚四
齓乙烯（PTFE或Gore-Tex)。每一類通路呈 A 及缺點。 峪，、有其自身的優點 =^路功能Μ為血㈣析人群中發病及住院治療的 管内二狹窄及後續血栓形成為特徵之靜脈新生▲ 、《生為造成透析移植失敗之主導性病理原因。 因此，對於預防及治療在損傷（例如血管 損傷’例“管再形成誘發之損傷，例二二： 形成程Γ植物中）後所發生之内膜増厚或再狹窄的血管再 療二路::易二斑塊之穩定化程序，或對於預防或治 不良，需要有效治療及藥物輪m 119075.doc -16 - 200815053 ^ 本务明之目標亦為提供一種含有本發明奈米粒子 酉予衣置’其允許在裝置之塗佈表面上或附近持續輸送 PDGF受體酪胺酸激酶抑制劑。 根據本發明之特定發現，提供·· (1)預防或治療需要其之哺乳動物之中空管中平滑肌細胞 增殖及遷移’或細胞增殖增加或細胞凋亡減少或基質沈積 增加之方法（例如基於導管之裝置），其包含使用本發明奈
米粒子局邛投與治療有效量之受體酪胺酸激酶抑制 劑0 (=)治療管壁中内膜增厚之方法，其包含自包含治療有效 里之PDGF文體酪胺酸激酶抑制劑之本發明奈米粒子的任 何基於導管之裝置（例如’留置旁通管、痛管或導管）或管 腔内醫療裝置來受控輸送。 ⑺穩定需要此穩定之患者之血管中易損斑塊的方法，其 包含自包含治療有效量之PDGF受體酪胺酸激酶抑制劑之 本發明奈米粒子的任何基於導管之裝置、管腔内醫療裝置 或外膜醫療裝置來受控輸送。 ⑷預防或治療再狹窄（例如糖尿病患者或高血屋 ，窄)之方法，其包含自包含治療有效量之 胺 酸激酶抑制劑之本發明奈米粒子的㈣基於導管之事置 官腔内醫療裝置或外膜醫㈣置來受控輸送。 :)穩定或修復患者之動脈或靜脈瘤的方法，其包含" 3治療有效量之PDGF受體酪 匕 ^ ^ 敦姆抑制劑之本發明奉 未粒子的任何基於導管装 不 、官㈣醫療裝置或外膜醫 119075.doc -17· 200815053 療裝置來受控輸送。 ⑺預防或治療患者之吻合增生之方法，#包 療有效量之PDGF受體酪胺酸激酶抑 3匕S治 子的杯妝文激蛛抑制劑之本發明奈米粒 子的任何基於導管之裝置、管腔 置來受控輸送。裝置或外膜醫療裝 W預防或治療患者之動脈(例如主動脈)旁路吻 法，其包含自包含治療有效量之PDGF受體路胺酸㈣
制劑之本發明奈米粒子的任何基於導管之裝置、管腔内醫 療裝置或外膜醫療裝置來受控輸送。 L W W藥物輸送裝置或系統，包含a)適於在中空管 用：投與的醫用裝置’例如基於導管之輸送褒置(例如留 置旁通管、瘺管或導管）或管腔内或中空管外之醫用裝 置’諸如外膜内所置放之植人物或勒，及b)可释放式固^ 於基於導管之輸送裝4或醫„置上的本發明奈米粒子。 該局部輸送裝置或系統可用於減少本文中所述之伴隨在 包括冠狀動膦、頸動脈、腎動脈、周邊動脈、腦動脈或任 何其他動脈或靜脈位置之任何血管位置中執行之血管再形 成、旁路或移植程序的血管損傷（例如狹窄、再狹窄或Z 架内再狹窄）以減少吻合狹窄或增生，包括在以下情況 下：具有或不具有聚四氟乙烯之動脈_靜脈透析通路，或 例如Gore-Tex移植且伴以或未伴以支架置放（stentin幻，或 聯合任何其他心臟或移植程序或先天血管介入。 局°卩彳又與較佳在血管病變部位或附近發生。 杈與可藉由以下途徑中之一或多者··經由導管或其他血 H9075.doc 200815053 管内輸送系統，鼻内，± ^ μ ^ 1 文《I管内，腹膜内或食道。中空管 包括循環系統脈管，諉士々 ^ 、， 血管（動脈或靜脈）、組織腔、淋 巴通道、包括消化管道 之肩化道、呼吸道、排泄系統管、 生殖系統管及管道、I#脾势 篮腔官等。局部投與或施用PDGF受 體路胺酸激酶抑制齋丨描彳址& - 制^如供该（等）PDGF受體酪胺酸激酶抑制 劑之集中輸送，達成不π ^ b _ • 可乂其他方式經由其他投與路徑獲 得之把組織中組織含量。另外，局部投與或施用可降低遠 m统毒性的風險。較佳根據本發明緊鄰或遠離局部治 療或置放支架之區域抑制或減輕平滑肌細胞增殖或遷移。 局邛輸送PDGF受體絡胺酸激酶抑制劑至中空管之方式 可藉由内部或外部物理輸送本發明奈米粒子至中空管。局 部輸运包括導管輸送系統、局部注射裝置或系統或留置裝 置。該等裝置或系統包括(但不限於)留置旁通管、瘺管、 導管、支架、管腔内套管、支架移植物、受控釋放基質、 聚合管腔内敷料或其他管内裝置、栓塞輸送粒子、細胞靶 瞻送諸如基於親和力之輸送、中空管周圍之内貼片、中空管 周圍之外貼片、中空管箍帶、外敷料、外支架套管及其類 似物。參見Eccleston等人。（1995) Interventi〇nal Cardi〇1〇gy
Monitor 1:33-40-41 ^ Slepian, N. J. (1996) Intervente. Cardiol. 1:103-116，或Regar E，Sianos G，Semiys pw. Stent development and local drug delivery· Br Med Bull 2001，59:227-48，該等揭示 案以引用方式併入本文中。較佳輸送裝置或系統滿足藥 理、藥物動力學及機械要求。較佳其亦適於滅菌。 根據本發明之支架可為任何支架，包括自擴展支架，或 119075.doc •19- 200815053 可藉由使氣球充氣來徑向擴展或藉由擴展構件來擴展的支 架，或藉由使用提供熱使得支架改變其大小的射頻來擴展 的支架。
輸送或施用PDGF受體酪胺酸激酶抑制劑可使用留置旁 通管、瘺管、支架或套管或鞘發生。可使用其中浸潰或併 有本發明奈米粒子之包含或塗佈有聚合物或其他生物相容 材料（例如多孔陶瓷，例如奈米多孔陶瓷）的支架。該等支 架可為生物可降解的或當意欲永久使用時可由金屬或合金 (例如Ni及Ti)或另一穩定物質製成。本發明奈米粒子亦可 截留於已經改質以含有微孔或通道的支架或移植體之金屬 中。同樣，由含有本發明奈米粒子之聚合物或其他生物相 容材料（例如上文揭示者)製成之内腔及/或遠腔塗層或外套 管亦可用於局部輸送PDGF受體酪胺酸激酶抑制劑。 ’’生物相容’’意謂不引發或最小程度引發包括（例如）血栓 形成及/或發炎之負性組織反應的材料。 容材料併入或固定於支架(或留置旁通管、瘺管或導管” 其可併入例如聚合物或聚合基質中且喷漢於支架外表面 上。本發明奈米粒子與聚合物材料之混合物可於溶劑或溶 劑混合物中製備且亦藉由浸潰塗佈、刷塗及/或浸潰/旋塗 :塗覆於支架表面，使溶劑蒸發以留下具有截留藥物之 、'、、在其中PDGF夂體酪胺酸激酶抑制劑自微孔、支桿或 通道輸送之支架的情況下，聚合物 〆 物，谷，夜可另外以外層方式 塗佈以控制咖受體赂胺酸激酶抑制劑的釋放；或者本 H9075.doc -20- 200815053 發明奈米粒子可包含於微孔、支桿或通道中且佐劑可併入 卜層或反之亦然。本發明奈米粒子亦可固定於支架 留置旁通管、瘺管或導管)之内層中且佐劑於外層中、，或 反之亦然。本發明奈米粒子亦可藉共價鍵(例如酯、醯胺 或野）連接至支架（或留置旁通管、瘺管或n 況涉及化學衍生。本發明奈米粒子亦可併入生物相容多孔 陶瓷塗層（例如奈米多孔陶瓷塗層）中。 聚合材料之實例包括親水性、疏水性或生物相容性生物 可降解材料，例如聚缓酸；纖維素聚合物；澱粉；膠原； 玻糖駿酸；明膠；基於内醋之聚酿或共聚§旨，例如聚丙交 酉旨；聚乙交聚丙交酉旨-乙交醋；聚己酸内酉旨；聚己酸 内醋-乙交_ ;聚（羥基丁酸聚（羥基戊酸聚羥基 (丁IS曰-共-戊酸酯）；聚乙交酯_共_碳酸丙二酯；聚（二氧 雜環己酮）；聚原酸酯；聚酸酐；聚胺基酸；多醣；聚磷 酸醋；聚磷酸酯-胺基甲酸酯；聚氰基丙烯酸酯；聚磷氮 烯；聚（醚·酯）共聚物，例如PE〇_PLLA，纖維蛋白；纖維 蛋白原；或其混合物；及生物相容非降解材料，例如聚胺 基甲酸酯；聚烯烴；聚酯；聚醯胺；聚乙酸内醯胺；聚醯 亞胺，聚氯乙烯，聚乙烯甲基醚；聚乙烯醇或乙浠醇/烯 烴共聚物，例如乙烯醇/乙烯共聚物；聚丙烯腈；乙烯基 單體與烯烴之聚苯乙烯共聚物，例如苯乙烯丙烯腈共聚 物，乙烯甲基丙烯酸甲酯共聚物；聚二甲基矽氧燒；聚 (乙烯·乙酸乙烯酯）；基於丙烯酸酯之聚合物或共聚物，例 如聚甲基丙烯酸丁酯，聚（甲基甲基丙烯酸羥乙酯）；聚乙 119075.doc -21 - 200815053 浠D比略σ定酮；氟化入 .r L A 〇物，堵如聚四氟乙烯；纖維素酯， 例如酷酸纖維素、硝酴 ^ -義、准素或丙酸纖維素；或其混合 物0
根據本★明之方法或在本發明之裝置或系統中，PDGF 受體路胺酸激酶抑制劑可被動式、主動式或在活化(例如 光活化）下溶離。 既定測試模型及尤其本文中所述之彼等測試模型可證明
本發明奈米粒子適合用於有效預防或治療血管平滑肌細胞 (SMC)生長疾病。 —如只例中所不’當與Α鼠主動脈及人類冠狀動脈動脈血 & MC起培養日十’載有榮光標記而非受體路胺酸 激酶抑制劑之奈米粒子快速進入幾乎所有smc中且於!小 時内到達核周區m卜’併人細胞中之該等奈米粒子顯 示在細胞質中之滞留延長至少達14天。如實例中進一步顯 示，〇.1 μΜ、10 μΜ&10 μΜ之非囊封伊馬替尼以劑量依 賴方式抑制PDGF誘導之SMC增殖/遷移；〇>1 μΜ之伊馬替 尼未顯示效果，但10 μΜ之伊馬替尼使PDGF誘導之反應正 規化。以含有O.i μΜ之伊馬替尼之奈米粒子共處理或預處 理完全使PDGF誘導之SMC增殖/遷移正規化。此證明與非 囊封之游離伊馬替尼相比，奈米粒子化伊馬替尼之抑制效 能至少強100倍。 【實施方式】 實例之詳細論述 奈米粒子之細胞吸收與細胞内分佈 119075.doc -22- 200815053 發^標記使得奈米粒子之細胞吸收易於由螢光顯微鏡俄 +务現/與大鼠线脈及人類冠狀動脈動脈讀—起培 養時，螢光囊封之奈米粒子顯示細胞内輸送之能力極好 (圖1)。缺，當SMC與空白奈米粒子或僅螢光一起典育 時’未偵測到榮光。大部分（>9G%)奈米粒子快速進入細 胞’且併人率持續穩定直至24小時（® 2);當細胞盘〇5 mg/mL之PEG_PLGA奈米粒子—起培育時，輸送率在μ mm時為約100%，在3〇 min時為約98%，在6〇 mb時為約 88% ’在6小時時為約96%，且在μ小時時為約％❶/。。在此 研究過程中細胞可存活。關於SMC合併奈米粒子之時程， 發現奈米粒子經由細胞内吞途徑吸收且在細胞質中，尤其 在核周區域中保持穩定。長期追蹤研究顯示培育奈米粒子 3 0分鐘且洗滌後，核周圍之不連續螢光圖案完整保持直至 14天為止。 PDGF-BB誘導之SMC增殖及遷移受伊馬替尼及載有伊馬 替尼之PEG-PLGA奈米粒子抑制 進一步發現以10 ng/ml之10 ng/ml PDGF-BB刺激人類冠 狀動脈動脈血管SMC導致細胞數顯著增加。游離伊馬替尼 以劑量依賴方式減少PDGF-BB誘導之SMC增殖。1〇 μΜ伊 馬替尼之濃度完全消除PDGF-BB誘導之對細胞增殖之刺激 效應。相反，以載有0.5 mg/ml伊馬替尼之PEG-PLGA奈米 粒子（含有0·1 μΜ伊馬替尼）同時處理與預處理均以與1〇 μΜ游離伊馬替尼類似之程度減弱pDGF_bb誘導之增殖。 換言之，在1 0 μΜ游離伊馬替尼與〇. 1 μΜ奈米粒子化伊馬 119075.doc -23- 200815053 替尼之間的抑制等級相當·2A)。 時處理與預處理均以與1 最後& aPDGF-BB誘導之遷移亦受大鼠主動脈SMC中 之游離伊馬f尼抑制。伊馬替尼於大鼠就中顯示劑量依 賴方式。以含有G.i μΜ伊馬替尼之pEG_pLGA奈米粒子同 μΜ游離伊馬替尼類似之程度防止 DGF ΒΒ誘V之遷移。亦即，在丨μΜ游離伊馬替尼與 μΜ奈米粒子化伊馬替尼之間的抑”級相當。與增殖檢
定、。果類似卩載有0·5 mg/ml伊馬替尼之叩g_plga奈米 粒子（含有G.i μΜ伊騎尼）同時處理或預處理之細胞減弱 PDGF-BB誘導之增殖。 PDGF誘‘之SMC增殖及遷移藉由用含有低濃度（〇1 _) 伊馬替尼之奈米粒子預處理而完全正規化。城，類似劑 量範圍之游離伊馬替尼未顯示效應。與游離伊馬替尼相 比，奈米粒子化伊馬替尼之抑制效能強1〇〇倍。 根據本發明之特定發現’本發明亦提供治療包括人類之 /皿i動物之方法H冶療有效劑量之本發明奈米粒子投 與該罹患血管平滑肌細胞生長疾病之溫血動物。 本發明亦係關於包含本發明奈米粒子尤其用於治療血管 平滑肌細胞生長疾病的醫藥組合物。 本發明奈米粒子類似地由諸如内皮細胞、白細胞、心肌 細胞及纖維母細胞吸收，其使得可將本發明奈米粒子應用 於若干種難治疾病。因此，在本發明之更廣態樣中，本發 明奈米粒子亦可用於治療動脈粥樣硬化（心肌梗塞、腦梗 塞、周邊動脈疾病）、靜脈移植失敗、移植後動脈硬化、 119075.doc -24- 200815053 器官纖維化及動脈瘤。 醫藥組合物包含本發明奈米粒子及適於局部、經腸(例 如經口或經直腸)或非經腸投與且可為無機或有機、固體 或液體之醫藥學上可接受之载劑。對於經口投與，尤其使 用包含本發明奈米粒子及例如乳糖、葡萄糖、嚴糖、： 糖醇、山梨糖醇、纖維素及/或甘油之稀釋劑，及/或例如 矽酸、滑；5、硬脂酸或其鹽（諸如硬脂酸鎮或硬脂酸約）之 Ό閏及/或聚乙二醇及/或穩定劑。鍵劑亦可包含黏合 劑及（若需要）崩解劑、吸附劑、染料、調味料及甜味劑。 本發明奈米粒子亦可以可非經腸投與組合物形式或輸注溶 、、弋使用°亥專溶液包含例如穩定劑、防腐劑、濕潤劑 及/或礼化劑之賦形劑，調節滲透壓之鹽及/或緩衝劑。本 發明之醫藥組合物以自身已知之方式製備，且包含約ι% 至100%，尤其約1%至約20%之活性成份。 待使用之本發明奈米粒子之劑量範圍視熟習此項技術者 已头之口素而疋，該等因素包括溫血動物種類、體重及年 齡、投與方式、待使用之特定物質及待治療之疾病狀態。 除非本文另有所述，否則本發明奈米粒子較佳每天投與一 至四次。 以下實例用以說明本發明，而不限制本發明之範圍。 實例1 ··奈米粒子之製備 載有螢光標記或伊馬替尼之PEG孔0八奈米粒子由溶劑 擴散法製備。將具有75:25之^(}莫耳比&2〇〇〇〇iMw之疏 尺丨生來（D，L_乳酸.共β羥基乙酸）(PLGA)、具有30,〇〇〇_ H9075.doc -25 - 200815053 70,000之MW之聚乙烯醇（PVA)、螢光標記香豆素-6溶解於 乙酸乙醋中。將水溶性聚乙二醇（購自Aldrich Chemical Co·之平均分子量在2,000至20,000範圍内的PEG)首先溶解 於水中且然後於溶解PLGA之有機相中乳化。將PEG-PLGA 之油相溶液慢慢地倒入包含PVA之水溶液中並且利用微尖 探針音波器來乳化。PEG-PLGA共聚物溶液亦包含0.05% (w/v)香豆素-6或5% (w/v)螢光素異硫氰酸酯（FITC)作為螢 光標記或15%(w/v)伊馬替尼用於分別製備載有螢光標記或 伊馬替尼之PEG-PLGA奈米粒子。然後將產生之水包油乳 液在室溫下攪拌。將獲得之PEG-PLGA奈米粒子由離心收 集並且用微孔過濾水洗滌3次以除去過量的乳化劑。 實例2 :螢光顯微術 除非另外指示，否則將大鼠主動脈SMC(Toyobo)於補充 有 10% FBS(Equitech-Bio，Inc.)之 DMEM(Sigma)中培養。 將人類冠狀動脈 SMC(Cambrex Bio Science Walkersville， Inc.)於 SmGM-2(Cambrex Bio Science)中培養。使用介於第 4繼代至第8繼代之間的每種細胞。將大鼠主動脈SMC接種 於分室蓋玻片上並且在37°C /5% C02環境下培育直至細胞 接近於匯合。在實驗當天，生長培養基替換為載有香豆 素-6之PEG-PLGA奈米粒子懸浮液培養基（0·5 mg/ml)且然 後再培育1小時。在實驗結束時，細胞用PBS洗滌三次以便 消除未併入細胞之過量奈米粒子。然後，以1%甲醛/PBS 緩衝液固定細胞並且將核用碘化丙啶（PI)對比染色。由螢 光顯微術評價載有香豆素-6之PEG-PLGA奈米粒子的細胞 119075.doc -26- 200815053 吸收。 或者，將大鼠主動脈SMC與載有FITC之PEG-PLGA奈米 粒子（0.5 mg/ml) —起培育30分鐘。然後丟棄培養基並且用 PBS洗滌三次並且繼之以用新鮮的培養基培育。此後，觀 察細胞14曰。 實例3 :奈米粒子之細胞吸收及細胞内分佈 _ 將大鼠主動脈SMC接種於48-孔培養板上至每孔lxlO5個 細胞（每孔n=4)。載有香豆素-6之PEG-PLGA奈米粒子懸浮 ⑩ 液培養基以在0.1 mg/ml至0.5 mg/ml範圍内之最後濃度添 加至細胞中。為檢查培育時間對於細胞内吸收之影響，持 續時間自5分鐘至24小時各異。在不同的時間點，除去包 含奈米粒子之培養基，並且用PBS洗滌細胞三次。細胞以 1%甲醛/PBS緩衝液固定。用顯微鏡記錄微分干涉差（DIC) 及螢光影像。將影像數位化且用Adobe Photoshop及Scion Image軟體分析。計算各場中螢光陽性細胞的總數及總細 0 胞數。細胞吸收百分比由各場中螢光陽性細胞佔總細胞之 百分比來評定。細胞吸收百分比由下式評定：螢光陽性面 積/細胞表面積x 10 0。 • 實例4 : SMC增殖檢定 將人類冠狀動脈動脈血管SMC(Cambrex Bio Science Walkersville，Inc)於具有 10% FBS 之 SM-BM 中以每孔 5xl03 個細胞（每組n=6)接種於48-孔培養板（FALCON 354506 BIOCOAT CELL WARE人類纖維結合蛋白）中。24小時後， 使細胞於無血清之培養基中餓乏72小時以便獲得靜止的非 119075.doc -27- 200815053 分裂細胞。饑餓試驗後，添加重組PDGF-BB(Sigma)10 ng/ml。亦向各孔中添加不同濃度之伊馬替尼（〇·! μΜ、；[ μΜ、10 μΜ)或載有伊馬替尼之pEG-PLGA奈米粒子（0.5 mg/rnl)。在一些實驗中，在最後24小時向細胞中添加載有 伊馬替尼之PEG-PLGA奈米粒子（0.5 mg/ml)。用PBS洗滌 此等孔’隨後進行PDGF刺激。四天後，細胞用甲醇固定 並且用Diff-Quick染色液（Baxter)染色。一個不瞭解實驗方 案的觀察者在顯微鏡下計算每板細胞數目以量化SMC增 殖。載有伊馬替尼之PEG-PLGA奈米粒子（0.5 mg/ml)相當 於0 · 1 μΜ濃度之游離伊馬替尼。 實例5 : SMC遷移檢定 如先前所述（Ono H，Ichiki Τ等人Artedoscler Thromb Vase Biol. 2004; 24:1634-9·)，大鼠主動脈SMC之遷移用收 容具有8·0-μηι孔之經膠原預塗之聚碳酸酯膜的B〇ydeil室型 細胞遷移檢定套組（Chemicon)來評定。SMC生長至半匯合 且然後使得其在遷移以前在無血清培養基中靜止24小時。 細胞（1 X 105細胞/毫升）添加至膜之上室中（每組n=6)並且使 其遷移穿過孔。使細胞經30分鐘附接於膜上，隨後添加伊 馬替尼（0.1 μΜ、1 μΜ、10 μΜ)或載有伊馬替尼之peg· PLGA奈米粒子（〇·5 mg/ml)。在一些實驗中，在最後24小 時向細胞中添加載有伊馬替尼之PEG-PLGA奈米粒子（〇.5 mg/ml)。用PBS洗滌此等細胞，隨後進行PdGf刺激。然後 將SMC於下室中暴露於PDGF-BB(l〇 pg/mi)中4小時，之後 使用棉棒自上室除去未遷移之細胞。將遷移至過濾器下侧 119075.doc • 28 - 200815053 之SMC固疋在甲醇中，用Diff_Quick染色液（如如）染色， 並且在顯微鏡下計數以量化SMC遷移。 【圖式簡單說明】 圖 1A ·· 當與大鼠主動脈及人類冠狀動脈SMC 一起培養3〇分鐘 守載有曰豆素-6之peg_plga奈米粒子顯示穿過細胞膜 及到達核周區域的能力極好。核以碘化丙啶（PI)對比染 色尺度5。大部分奈米粒子快速進入細胞：i 5 min 穿過細胞膜時輸送率為約60%且在丨小時内到達核周區 域。 圖1B :細胞吸收米粒子的效率 觀察到細胞吸收與PEG-PLGA奈米粒子懸浮液之濃度無 關。細胞吸收百分率藉由用電腦辅助顯微鏡量測螢光陽性 區域/細胞表面積X100。數據為平均值土SEM(n=4)。 PDGF-BB誘導之SMC增殖及遷移受伊馬替尼及載有伊馬 替尼之PEG-PLGA奈米粒子抑制。 圖 2A ·· 用10 ng/ml PDGF-BB刺激人類冠狀動脈血管SMC導致細 胞數顯著增加。伊馬替尼劑量依賴性地減少pDGF_BB誘導 之SMC增殖。10 μΜ伊馬替尼之濃度完全消除1>〇(}17_]68對 細胞增殖之刺激效應。相反，以載有〇.5 mg/ml伊馬替尼之 PEG-PLGA奈米粒子（含有〇·ΐ μΜ伊馬替尼）同時處理或預 處理之細胞減弱PDGF-BB誘導之增殖。數據為平均值 士SEM(n=6)。*Ρ<0·01(對照），p<〇 〇1(pDGF)。 119075.doc -29- 200815053
圖2B PDGF-BB誘導之大鼠主動脈SMC遷移係在Transwell遷移 室中量測。伊馬替尼顯示對於PDGF-BB依賴性遷移之劑量 依賴性抑制效應。與增殖檢定結果類似，以載有0.5 mg/ml 伊馬替尼之PEG-PLGA奈米粒子（含有0.1 μΜ伊馬替尼）同 時處理或預處理之細胞減弱PDGF-BB誘導之增殖。 圖3 PEG-PLGA奈米粒子細胞毒性之MTS檢定。條形圖顯示 m — 與載有指定濃度之FITC之PEG_PLGA奈米粒子一起培育48 小時的人類冠狀動脈血管SMC之生存力。數據為平均值 土SEM(n=5)。 PDGF誘導之SMC增殖及遷移藉由用含有低濃度（0.1 μΜ) 伊馬替尼之奈米粒子預處理而完全正規化。相反，類似劑 量範圍之游離伊馬替尼未顯示效應。與游離伊馬替尼相 比，奈米粒子化伊馬替尼之抑制效能強100倍。
119075.doc -30-
Claims (1)
- 200815053 十、申請專利範圍： 1. 一種奈米粒子’其包含PDGF受體酪胺酸激酶抑制劑。 2·如請求項1之奈米粒子，該PDGF受體酪胺酸激酶抑制劑 在2〇°C具有介於約2.5 g/l〇〇 ml與250 g/l00如之間的水 溶解度。 • 3.如請求項1之奈米粒子，其中該PDGF受體酪胺酸激酶抑 制劑為式I之N-苯基-2-嘧啶-胺衍生物其中Ri為4-吼嗪基；1 -甲基-1 H-吼洛基；胺基取代或胺基_低 碳烷基取代之苯基，其中該胺基在各種情況下呈游 離、烷化或醯化形式·，在五員環碳原子處鍵結之1H_ °引11朵基或1 Η-咪吐基；或在環碳原子處鍵結之未經取 代或低破烧基取代之σ比咬基且其未經取代或在氮原子 處經氧取代； R2及R3各自彼此獨立地為氫或低碳烧基； 基團R4、R5、R6、117及R8中之一或兩者各自為硝基、I 基取代之低碳烷氧基或式II之基團 -N(R9)-C(=X)-(Y)n.R10 (π)， 其中 119075.doc 200815053 R9為氫或低碳烷基， X為側氧基、硫基、亞胺基、N-低碳烷基-亞胺基、辟 基或0_低碳烷基-肟基， Y為氧或基團NH， η為〇或1且 Rio為具有至少5個碳原子之脂族基團，或芳族、芳族_ 脂族、環脂族、環脂族-脂族、雜環或雜環_脂族基 團， _ 且其餘基團R4、Rs、I、R?及Rs各自彼此獨立地為 氫，未經取代或經游離或烷化胺基、哌嗪基、哌啶 基、吼咯啶基或經嗎啉基取代之低碳烷基，或低碳 烧si基，三氟甲基，游離、醚化或酯化羥基，游 離、烷化或醯化胺基，或游離或酯化羧基， 或具有至少一個形成鹽之基團之該化合物之鹽。 4·如請求項3之奈米粒子，其中該式1之义苯基_2•嘧咬-胺 _ 竹生物為{5-[4-(4-曱基-派嗓基_曱基）_苯曱隨基胺基]_ 2-曱基苯基）-4-(3-吡啶基）-2-嘧啶-胺}(伊馬替尼 (Imatinib)) 〇 ， 5 ·如請求項4之奈米粒子，其中伊馬替尼係以其單甲磺酸 鹽形式使用。 6.如請求項1至5中任一項之奈米粒子，其中該等奈米粒子 具有約2.5 nm至約1〇〇〇 nm之平均直徑。 7·如請求項1至6中任一項之奈米粒子，其中該等奈米粒子 具有約5 nm至約500 nm之平均直徑。 119075.doc 200815053 8·如請求項1至7中任一項之奈米粒 Α人 丁头肀該等奈米粒子 包含生物可降解之聚酯。 9 ·如請求項1至7中任一頊之泰半私2 ^ t W貞％未粒子，其巾料奈米粒子 包含聚乙二醇（PEG)改質之聚_ 内又軺_乙父酯共聚物 (PLGA)奈米粒子。 ίο. 一種藉由應用球形結晶技術來製備如請求項丨至9中任一 項之具有50 nm平均直徑之奈米粒子的方法。 11· 一種治療包括人類之溫血動物 初初t万法，其中將治療有效 劑量之如請求項1至9中任一項太 π <不木粒子投與罹患A管 平滑肌細胞生長疾病之溫Α動物。 12·-種如請求項⑴中任—項之奈米粒子之用途，其係用 於製造供治療*管平滑肌細胞生長疾病之醫藥組合物。 η.如請求項u之方法或如請求項12之用途，其中該等企管 平滑肌細胞生長疾病係選自再狹窄、動脈粥樣硬化金管 疾病及原發性肺動脈高壓。 14 · 一種醫藥組合物，豆肖合士主七 切八巴3如睛求項1至9中任一項之奈米 粒子。 15.一種如請求項⑴中任一項之奈米粒子用於製造醫藥產 -之用途，該醫藥產品係用以穩定需要該穩定之個體血 e中之易損斑塊，用以預防或治療糖尿病患者之再狭 窄，或用以預防或降低有此需求之個體與插入或修復留 置旁通管、瘺管或導管相關之血管通路功能不良。 16. -種用以預防或降低有此f求之哺乳動物與在靜脈或動 脈中插入留置旁通管、瘺管或導管或修復該留置旁通 119075.doc 200815053 管、瘤管或導管相關，+、 或/、焉際治療相關的血管通路六 能不良的方法，其包含_ 略功 八匕3向该個體投與有效量之如請 1至9中任一項之奈米粒子。 、 ’其係用於透析患者。 17.如請求項16或17之用途或方法 18. 種藥物輸达裝置或系統，其包含i)適於在中空管中 部施用或給藥的醫疼梦¥ ° 旧商縻衣置及H)可釋放式固定於該藥物輪 送裝置或系統的如請求項㈤中任一項之奈米粒子。19, 種治療血管壁之内膜增厚之方法，其包含自包含如請 求項1至9中任-項之奈米粒子的任何基於導管之裳置或 管腔内醫療裝置控制輸送治療有效量之pDGF受體路胺 酸激酶抑制劑。 2〇. -種穩定需要該穩定之個體血管中之易損斑塊的方法， 其包含自包含如請求们至9中任一項之奈米粒子的任何 基於導管之裝置、管腔内醫療裝置或外膜醫療裝置控制 輸送治療有效量之PDGF受體酪胺酸激酶抑制劑。 21· —種預防或治療再狹窄之方法，其包含自包含如請求項 1至9中任一項之奈米粒子的任何基於導管之裝置、管腔 内醫療裝置或外膜醫療裝置控制輸送治療有效量Z PDGF受體酪胺酸激酶抑制劑。 22· —種穩定或修復個體之動脈或靜脈瘤之方法，其包含自 包含如清求項1至9中任一項之奈米粒子的任何基於導管 之裝置、管腔内醫療裝置或外膜醫療裝置控制輸送治療 有效量之PDGF受體酪胺酸激酶抑制劑。 23 · —種預防或治療個體之吻合增生之方法，其包含自包含 119075.doc 200815053 如請求項1至9中任一項之奈米粒子的任何基於導管之壯 置、管腔内醫療裝置或外膜醫療裝置控制輸送治療有= 量之PDGF受體酪胺酸激酶抑制劑。 24· -種預防或治療個體之例如主動脈之動脈旁路吻人的方 包含；包含如請求項1至9中任-項之奈米二子的 壬7土於導官之裝置、管腔内醫療裝置或外膜醫療裝置 &制輸n療有效量之PDGF受龍胺酸激酶抑制劑:119075.doc
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| WO2009042803A1 (en) | 2007-09-25 | 2009-04-02 | Teva Pharmaceutical Industries Ltd. | Imatinib compositions |
| JP2012512175A (ja) * | 2008-12-15 | 2012-05-31 | バインド バイオサイエンシズ インコーポレイテッド | 治療薬を徐放するための長時間循環性ナノ粒子 |
| WO2010101240A1 (ja) * | 2009-03-06 | 2010-09-10 | 国立大学法人岡山大学 | 生分解性多孔質中空微粒子、その製造方法および用途 |
| RU2469729C1 (ru) * | 2011-08-26 | 2012-12-20 | Учреждение Российской академии медицинских наук Научно-исследовательский институт кардиологии Сибирского отделения РАМН | Средство для деструктуризации атеросклеротических образований, формирующихся на стенках кровеносных сосудов |
| WO2013124774A1 (en) | 2012-02-21 | 2013-08-29 | Ranbaxy Laboratories Limited | Stable dosage forms of imatinib mesylate |
| 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 |
| US10143700B2 (en) | 2013-02-19 | 2018-12-04 | Amrita Vishwa Vidyapeetham | Nanoparticle formulations for delivering multiple therapeutic agents |
| JP6799201B2 (ja) | 2013-07-31 | 2020-12-16 | アヴァリン ファーマ インク． | エアロゾルチロシンキナーゼ阻害剤の化合物、及びその使用 |
| EP3409772B1 (en) * | 2016-01-29 | 2023-06-28 | National University Corporation Hokkaido University | Intracellular substance transport system and use thereof |
| CN114514016A (zh) | 2019-05-16 | 2022-05-17 | 埃渃维特治疗学公司 | 伊马替尼调配物、制造和其用途 |
| US11464776B2 (en) | 2019-05-16 | 2022-10-11 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
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| CA2550702A1 (en) | 2007-09-24 |
| BRPI0602338A (pt) | 2007-12-11 |
| PE20071337A1 (es) | 2008-01-08 |
| WO2007119601A3 (en) | 2008-02-21 |
| KR20070096729A (ko) | 2007-10-02 |
| CL2007000781A1 (es) | 2008-03-14 |
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| WO2007119601A2 (en) | 2007-10-25 |
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