TW201922253A - 調節激酶之化合物之調配物 - Google Patents
調節激酶之化合物之調配物 Download PDFInfo
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- TW201922253A TW201922253A TW107138011A TW107138011A TW201922253A TW 201922253 A TW201922253 A TW 201922253A TW 107138011 A TW107138011 A TW 107138011A TW 107138011 A TW107138011 A TW 107138011A TW 201922253 A TW201922253 A TW 201922253A
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Abstract
Description
揭示了適用於治療疾病之生物活性化合物之新組合物及製造此類組合物之方法。
(R)-N-(3-(5-(2-環丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-3-氟吡咯啶-1-磺醯胺為BRAF之突變形式的強力抑制劑,且可適用於治療BRAF介導之疾病,諸如轉移性黑色素瘤、甲狀腺癌及結腸直腸癌。化合物及其合成已描述於WO 2012/109075及WO 2016/191303中。開發此及其他相關生物活性分子之有效且安全的調配物仍令人關注。
本發明係關於包含具有下式之化合物I的固態分散體:
化合物I,
其中化合物I為實質上非晶形的。
化合物I,
其中化合物I為實質上非晶形的。
在另一實施例中,本發明之固態分散體進一步包含一或多種賦形劑。
在另一實施例中,本發明之固態分散體進一步包含一或多種助溶劑。
在本發明之固態分散體之另一實施例中,化合物I在其固體狀態下以分子形式分散於由乙酸丁二酸羥丙基甲基纖維素 (HMPCAS)形成之聚合物基質內。
本發明亦係關於製造本發明之固態分散體的方法。
本發明亦係關於藉由本發明之方法製得之固態分散體。
本發明亦係關於藉由由突變BRAF (包括BRAF V600E)介導之疾病或病狀治療受試者的方法,其包含治療向該等受試者投與本發明之有效量的固態分散體。
本發明亦係關於治療由突變BRAF (包括BRAF V600E)介導之疾病或病狀之受試者的方法,其包含與一或多種CYP抑制劑(包括CYP3A4抑制劑)組合地向該等受試者投與本發明之固態分散體中之任一種。
本發明之額外態樣及實施例將自以下實施方式及申請專利範圍而顯而易見。
相關申請案之交互參照
本申請案主張2017年10月27日提交之美國臨時申請案第62/578,334號之35 U.S.C. §119(e)下的權益,其特此以全文引用之方式併入。
定義
定義
除非另外明確指示,否則如本文所用之以下定義應適用。
除非相反地清楚地指示,否則在本文中所描述之式內(在提供之結構內或在與結構相關之變數之定義內)指定之所有原子意欲包括其任何同位素。應理解,對於任何給定原子,同位素可基本上以根據其天然出現率之比率存在,或一或多種特定原子可使用熟習此項技術者已知之合成方法相對於一或多種同位素增強。因此,氫包括例如1
H、2
H、3
H;碳包括例如11
C、12
C、13
C、14
C;氧包括例如16
O、17
O、18
O;氮包括例如13
N、14
N、15
N;硫包括例如32
S、33
S、34
S、35
S、36
S、37
S、38
S;氟包括例如17
F、18
F、19
F;氯包括例如35
Cl、36
Cl、37
Cl、38
Cl、39
Cl;及類似者。
「BRAF」為編碼被稱為BRAF之蛋白激酶的人類基因。BRAF突變相關之疾病可為BRAF V600突變及非V600突變。BRAF V600突變導致BRAF中位置600 (纈胺酸)處之胺基酸取代。
如本文中所使用,術語「治療(treat)」、「治療(treating)」、「療法(therapy)」、「療法(therapies)」及類似術語係指如本文中所描述以有效地預防、緩解或改善疾病或病狀之一或多個症狀(亦即,適應症)及/或有效地延長所治療之受試者之存活期的量投與材料,例如任一或多種化合物。
如本文所使用,術語「膠囊調配物」係指本發明中之固態分散體中之任一種的膠囊。
如本文所使用,術語「錠劑調配物」係指本發明中之固態分散體中之任一種的錠劑。
如本文所用,術語「受試者」係指用如本文中所描述之化合物治療之活有機體,包括但不限於任何哺乳動物,諸如人類、其他靈長類動物、競技動物、商業相關動物(諸如牛)、農畜(諸如馬)或寵物(諸如犬及貓)。
如本文所使用,在定量量測之情形下使用之術語「約」意謂所指示之量±10%。舉例而言,「約2:8」將意指1.8-2.2:7.2-8.8。
如本文中所使用,術語「非晶形」係指材料在分子級下不具有長距規則且取決於溫度可展現固體或液體之物理特性的狀態。此類材料通常不產生獨特X射線繞射圖案,且在展現固體特性同時,更正式地描述為液體。在加熱時,發生自固體至液體特性之改變,特徵為狀態之改變,通常為二階(玻璃轉變)。
如本文中所使用,如本文中所使用之術語「實質上非晶形」意欲意謂存在於組合物中之化合物之大於60%;或大於65%;或大於70%;或大於75%;或大於80%;或大於85%;或大於90%;或大於95%;或大於99%呈非晶形式。「實質上非晶形」亦可指具有不超過約20%結晶性,或不超過約10%結晶性;或不超過約5%結晶性;或不超過約2%結晶性;或不超過約1%結晶性之材料。
如本文中所使用,術語「固態分散體」意謂具有至少兩種組分之任何固體組合物。在某些實施例中,如本文中所揭示之固態分散體包括活性成份(例如,化合物1);其較佳分散於至少一種其他組分(例如,聚合物,諸如HMPCAS)當中。在某些實施例中,如本文中所揭示之固態分散體為醫藥分散體,其包括至少一種醫藥或生物活性成份(例如,化合物1)。在一些實施例中,固態分散體包括藉由聚合物以分子形式分散之化合物I。較佳地,固態分散體以一相體系形式存在。
如本文中所使用,如本文中所使用之術語「結晶」係指材料在分子級下具有規則有序內部結構且產生具有經定義峰值之獨特X射線繞射圖案的固相。此類材料在充分加熱時亦將呈現液體之特性,但自固體至液體之改變的特徵在於相變,通常為一級(熔點)。
如本文中所使用,如本文中所使用之術語「黏合劑」係指可用以將載劑之活性及惰性組分黏合在一起以維持黏性且離散部分的任何醫藥學上可接受之膜。黏合劑之非限制性實例包括羥丙基纖維素、羥基丙基甲基纖維素、普維酮、共聚普維酮、乙基纖維素及其組合。
如本文中所使用,如本文中所使用之術語「崩解劑」係指在添加至固體製劑後促進其在投與之後破裂或崩解且准許儘可能高效地釋放活性成份以允許其快速溶解的物質。崩解劑之非限制性實例包括羥基乙酸澱粉鈉、交聯羧甲纖維素鈉、交聯普維酮改質之玉米澱粉及其組合。
如本文中所使用,如本文中所使用之術語「潤滑劑」係指添加至粉末摻合物以防止經壓緊粉末物質在製錠或囊封製程期間黏附至設備之賦形劑。其有助於錠劑從壓模中彈射出,且可改良粉末流。潤滑劑之非限制性實例包括硬脂酸鎂、硬脂酸、矽石、礦物油及其組合。
如本文中所使用,如本文中所使用之術語「滑動劑」係指在錠劑及膠囊調配物中使用以改良錠劑壓縮期間之流動特性且產生防結塊效果的藥劑。滑動劑之非限制性實例包括膠態二氧化矽、纖維素、氧化鎂及其組合。
如本文中所使用,如本文中所使用之術語「% w/w」係指以包含組分之組合物之總重量計的組分重量。舉例而言,若組分A以50% w/w之量存在於100 mg組合物中,則組分A以50 mg之量存在。
如本文中所使用,如本文中所使用之術語「界面活性劑」係指減少液體與固體之間的表面張力之物質,其可改良活性劑之濕潤或改良活性劑之溶解度。界面活性劑之非限制性實例包括泊洛沙姆(poloxamer)407及月桂基硫酸鈉。
如本文中所使用,如本文中所使用之術語「助溶劑」係指能夠增加活性劑之溶解度的物質。助溶劑之非限制性實例包括聚乙二醇及共聚普維酮。
如本文中所使用,如本文中所使用之術語「滲透原」係指較佳出於向整個核心分配水之目的將水抽吸至錠劑核心中以使得核心中所含之活性成份可釋放的水溶性組分。滲透原之非限制性實例包括氯化鈉及氯化鉀。
如本文中所使用,術語「以分子形式分散」係指藉由聚合物無規分佈化合物(例如,化合物I)。在某些實施例中,化合物以最終分部狀態存在於聚合物中。參見例如M.G. Vachon等人,J . Microencapsulation
14:281-301 (1997)及Vandelli等人,J . Microencapsulation
, 10:55-65 (1993)。在一些實施例中,化合物(例如,化合物I)可在其固體狀態下分散於由聚合物形成之基質內,使得化合物以其非晶形式固定。可以各種方式,例如藉由具有單一玻璃轉變溫度之所得固體分子錯合物來證明化合物是否以分子形式分散於聚合物中。
在作為或可為調節劑之化合物之使用、測試或篩選之情形中,術語「接觸」意謂使得化合物足夠接近特定分子、錯合物、細胞、組織、生物或潛在結合交互作用之其他指定材料及/或可在化合物與其他指定材料之間進行化學反應。
術語「醫藥學上可接受」指示在考慮欲治療之疾病或病狀及各別投藥途徑的情況下,所指示之材料不具有將使相當謹慎之醫學從業者避免向患者投與該材料之特性。舉例而言,通常要求此類材料基本上無菌,例如用於可注射劑。
在本文之情形下,術語「治療有效」或「有效量」指示材料或材料之量有效地預防、緩解或改善疾病或醫學病狀之一或多種症狀及/或延長所治療之受試者的存活期。在某些實施例中,化合物I之「治療有效量」係指抑制諸如BRAF V600E之突變BRAF激酶所必需的此類時間段之此類劑量及/或投與。此外,治療有效量可為整體治療上有利效果勝過毒性或非所要副作用的量。化合物I之治療有效量可根據所治療之受試者之疾病病況、年齡及重量而變化。因此,劑量方案通常以各特例調整個體需求且在此項技術內。在某些實施例中,向成人投與化合物I之適當每日劑量可為約50 mg至約3200 mg;或約75 mg至約2000 mg,儘管在指示時可超出上限及下限。化合物I之每日劑量可作為單次劑量、以分次劑量或針對非經腸投藥投與,其可作為皮下注射給予。
在本文之情形下,術語「協同有效」或「協同作用」指示治療上有效的兩種或多於兩種化合物在組合使用時提供大於基於各化合物單獨使用之作用預期的累加作用的改良治療作用。
如本文中所使用,術語「調節」係指改變生物活性之作用,尤其與特定生物分子(諸如蛋白激酶)相關聯之生物活性。舉例而言,特定生物分子之促效劑或拮抗劑藉由增加(例如,促效劑、活化劑)或減小(例如,拮抗劑、抑制劑)生物分子(諸如酶)之活性來調節彼生物分子(例如,酶)之活性。此類活性通常分別針對抑制劑或活化劑之化合物相對於例如酶的抑制濃度(IC50
)或激發濃度(EC50
)來指示。
如本文中所使用,術語「混合」或「摻合」可互換且意謂組合兩種或以上物質。
本發明之組合物可用於經口投與受試者以用於治療由BRAF介導之疾病之BRAF及突變形式調節的疾病及病狀。在某些實施例中,本發明之組合物具有改良之生物可用性。
固態分散體
固態分散體
實施例1係關於一種包含具有下式之化合物I的固態分散體:
化合物I,
其中化合物I為實質上非晶形的。
化合物I,
其中化合物I為實質上非晶形的。
化合物I描述於美國專利公開案第2014/0128373號中。化合物I為極強力突變BRAF激酶抑制劑(在本文中亦被稱作突變BRAF),其包括BRAF V600E,且亦為特別強的矛盾阻斷劑(paradox breaker)。化合物I不活化MAPK路徑,其為典型的第一代BRAF V600E突變抑制劑。化合物I因此就此而言高度有利,且其已經測試及論證為可能適用於如美國專利公開案第2016/0339025 A1號中所描述之各種適應症。
實施例2係關於如實施例1之固態分散體,其中化合物I在其固體狀態下以分子形式分散於由乙酸丁二酸羥丙基甲基纖維素(HMPCAS)形成之聚合物基質內。
實施例3係關於如實施例2之固態分散體,其中該HMPCAS為HMPCAS-LF、HMPCAS-MF、HMPCAS-HF、HMPCAS-LG、HMPCAS-MG或HMPCAS-HG。
實施例4係關於如實施例3之固態分散體,其中該HMPCAS為HMPCAS-HG。
實施例5係關於如實施例2至4中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之重量比在約1:1至約1:4範圍內。
實施例6係關於如實施例2至5中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之該重量比在約1:2.5至約1:3.5範圍內。
實施例7係關於如實施例2至6中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之該重量比在約1:2.6至約1:2.9範圍內。
實施例8係關於如實施例2至7中任一項之固態分散體,其進一步包含一或多種界面活性劑。
實施例9係關於如實施例8之固態分散體,其中該一或多種界面活性劑為月桂基硫酸鈉(SLS)。
實施例10係關於如實施例8或9中任一項之固態分散體,其中化合物I在約15% w/w至約35% w/w範圍內;HMPCAS在約50% w/w至約85% w/w範圍內;且該一或多種界面活性劑在約1% w/w至約10% w/w範圍內。
實施例11係關於如實施例8至10中任一項之固態分散體,其中化合物I在約20% w/w至約30% w/w範圍內;HMPCAS在約60% w/w至約80% w/w範圍內;且該一或多種界面活性劑在約3% w/w至約7% w/w範圍內。
實施例12係關於如實施例8至11中任一項之固態分散體,其中化合物I在約22% w/w至約28% w/w範圍內;HMPCAS在約65% w/w至約75% w/w範圍內;且該一或多種界面活性劑在約4% w/w至約6% w/w範圍內。
實施例13係關於如實施例8至12中任一項之固態分散體,其中化合物I為約25% w/w;HMPCAS為約70% w/w;且該一或多種界面活性劑為約5% w/w。
實施例14係關於如實施例8至13中任一項之固態分散體,其進一步包含一或多種滑動劑;一或多種崩解劑;一或多種填充劑/黏合劑;及一或多種潤滑劑。
實施例15係關於如實施例14之固態分散體,其中該一或多種滑動劑在約0.5% w/w至約4% w/w範圍內;該一或多種崩解劑在約3% w/w至約9% w/w範圍內;該一或多種填充劑/黏合劑在約20% w/w至約40% w/w範圍內;該一或多種潤滑劑在約0.25% w/w至約1.25% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約45.75% w/w至約76.25% w/w範圍內。
實施例16係關於如實施例14之固態分散體,其中該一或多種滑動劑在約1.0% w/w至約3% w/w範圍內;該一或多種崩解劑在約4% w/w至約8% w/w範圍內;該一或多種填充劑/黏合劑在約25% w/w至約35% w/w範圍內;該一或多種潤滑劑在約0.5% w/w至約1.0% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約53% w/w至約69.5% w/w範圍內。
實施例17係關於如實施例14之固態分散體,其中該一或多種滑動劑在約1.5% w/w至約2.5% w/w範圍內;該一或多種崩解劑在約5% w/w至約7% w/w範圍內;該一或多種填充劑/黏合劑在約29% w/w至約33% w/w範圍內;該一或多種潤滑劑在約0.7% w/w至約0.8% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約56.7% w/w至約63.8% w/w範圍內。
實施例18係關於如實施例14至17中任一項之固態分散體,其中該一或多種滑動劑係選自由膠態二氧化矽、細微粉碎的二氧化矽、矽化微晶纖維素、氧化鎂、聚乙二醇及交聯羧甲纖維素鈉組成之群;該一或多種崩解劑係選自由碳酸氫鈉、羥基乙酸澱粉鈉、交聯羧甲纖維素鈉及交聯普維酮組成之群;該一或多種填充劑/黏合劑係選自由微晶纖維素、甘露糖醇、山梨糖醇、麥芽糊精、麥芽糖、糊精、二水合磷酸氫鈣、無水磷酸氫鈣、部分預糊化澱粉及磷酸三鈣組成之群;且該一或多種潤滑劑係選自由硬脂酸鎂、硬脂酸、棕櫚酸、硬脂酸鈣、巴西棕櫚蠟、經氫化植物油、礦物油、聚乙二醇及硬脂醯反丁烯二酸鈉組成之群。
實施例19係關於如實施例14至18中任一項之固態分散體,其中該一或多種滑動劑為膠態二氧化矽;該一或多種崩解劑為交聯羧甲纖維素鈉;該一或多種填充劑/黏合劑為甘露糖醇及微晶纖維素,且該一或多種潤滑劑為硬脂醯反丁烯二酸鈉。
實施例20係關於如實施例19之固態分散體,其中甘露糖醇與微晶纖維素之重量比在約2:3至約3:2範圍內。
實施例21係關於如實施例19之固態分散體,其中甘露糖醇與微晶纖維素之重量比在約1.1:1.0至約1.0:1.1範圍內。
實施例22係關於如實施例19至21中任一項之固態分散體,其中該微晶纖維素係選自由Avicel PH-101、Avicel PH-102、Avicel PH-105、Avicel PH-112及其組合組成之群。
實施例23係關於如實施例19至22中任一項之固態分散體,其中該微晶纖維素為Avicel PH-105與Avicel PH-101之組合。
實施例24係關於如實施例19至23中任一項之固態分散體,其中顆粒內微晶纖維素為Avicel PH-105,且顆粒外微晶纖維素為Avicel PH-101。
實施例25係關於如實施例24之固態分散體,其中Avicel PH-105與Avicel PH-101之比率為約1:1至約1:3。
實施例26係關於如實施例25之固態分散體,其中Avicel PH-105與Avicel PH-101之比率為約1:1.8至約1:2.2。
實施例27係關於如實施例1之固態分散體,其進一步包含一或多種助溶劑。
實施例28係關於如實施例27之固態分散體,其中該一或多種助溶劑係選自由以下各者組成之群:牛膽酸鈉、拉巴索(Labrasol)、泊洛沙姆、聚乙二醇、共聚普維酮、Transcutol P、丙二醇、Gelucire 44/14、HCO-60、乙醇、Cremophor EL、Tween 80、2羥丙基-β-環糊精及二甲亞碸。
實施例29係關於如實施例28之固態分散體,其中該一或多種助溶劑為泊洛沙姆407、聚乙二醇400及共聚普維酮。
實施例30係關於如實施例27至29中任一項之固態分散體,其進一步包含一或多種滑動劑;一或多種崩解劑;一或多種填充劑/黏合劑;一或多種潤滑劑;一或多種界面活性劑;及一或多種滲透原。
實施例31係關於如實施例30之組合物,其中化合物I在約5% w/w至約12% w/w範圍內;該一或多種助溶劑在約35% w/w至約65% w/w範圍內;該一或多種滑動劑在約0.5% w/w至約2% w/w範圍內;該一或多種填充劑/黏合劑在約8% w/w至約22% w/w範圍內;該一或多種界面活性劑在約0.5% w/w至約4% w/w範圍內;該一或多種崩解劑在約12% w/w至約24% w/w範圍內;該一或多種潤滑劑在約0.25% w/w至約3.0% w/w範圍內;且該一或多種滲透原在約2% w/w至約6% w/w範圍內。
實施例32係關於如實施例30之組合物,其中化合物I在約7% w/w至約10% w/w範圍內;該一或多種助溶劑在約45% w/w至約55% w/w範圍內;該一或多種滑動劑在約0.75% w/w至約1.5% w/w範圍內;該一或多種填充劑/黏合劑在約12% w/w至約18% w/w範圍內;該一或多種界面活性劑在約1% w/w至約3% w/w範圍內;該一或多種崩解劑在約16% w/w至約20% w/w範圍內;該一或多種潤滑劑在約0.50% w/w至約2% w/w範圍內;且該一或多種滲透原在約3% w/w至約5% w/w範圍內。
實施例33係關於如實施例30之組合物,其中化合物I在約7.5% w/w至約8.5% w/w範圍內;該一或多種助溶劑在約48% w/w至約52% w/w範圍內;該一或多種滑動劑在約0.9% w/w至約1.1% w/w範圍內;該一或多種填充劑/黏合劑在約14% w/w至約16% w/w範圍內;該一或多種界面活性劑在約1.5% w/w至約2.5% w/w範圍內;該一或多種崩解劑在約17% w/w至約19% w/w範圍內;該一或多種潤滑劑在約0.75% w/w至約1.25% w/w範圍內;且該一或多種滲透原在約3.5% w/w至約4.55% w/w範圍內。
實施例34係關於如實施例30至33中任一項之固態分散體,其中該一或多種界面活性劑為泊洛沙姆407、聚乙二醇400及共聚普維酮;該一或多種滑動劑係選自由膠態二氧化矽、細微粉碎的二氧化矽、矽化微晶纖維素、氧化鎂、聚乙二醇及交聯羧甲纖維素鈉組成之群;該一或多種崩解劑係選自由碳酸氫鈉、羥基乙酸澱粉鈉、交聯羧甲纖維素鈉及交聯普維酮組成之群;該一或多種填充劑/黏合劑係選自由微晶纖維素、甘露糖醇、山梨糖醇、麥芽糊精、麥芽糖、糊精、二水合磷酸氫鈣、無水磷酸氫鈣、部分預糊化澱粉及磷酸三鈣組成之群;該一或多種潤滑劑係選自由硬脂酸鎂、硬脂酸、棕櫚酸、硬脂酸鈣、巴西棕櫚蠟、經氫化植物油、礦物油、聚乙二醇及硬脂醯反丁烯二酸鈉組成之群;該界面活性劑為月桂基硫酸鈉;且該滲透原為氯化鈉。
實施例35係關於如實施例34之固態分散體,其中該一或多種界面活性劑為泊洛沙姆407、聚乙二醇400及共聚普維酮;該一或多種滑動劑為膠態二氧化矽;該一或多種崩解劑為碳酸氫鈉、交聯羧甲纖維素鈉及交聯普維酮;該一或多種填充劑/黏合劑為微晶纖維素及甘露糖醇;該潤滑劑為硬脂酸鎂;該界面活性劑為月桂基硫酸鈉;且該滲透原為氯化鈉。
實施例36係關於如實施例1至35中任一項之固態分散體,其中該組合物呈適用於口服劑量之錠劑形式。
實施例36(a)係關於實施例32,其中該錠劑含有50至500 mg之化合物I。
實施例36(b)係關於實施例32,其中該錠劑含有75至300 mg之化合物I。
實施例36(c)係關於實施例32,其中該錠劑含有75至200 mg之化合物I。
實施例36(d)係關於實施例32,其中該錠劑含有75至150 mg之化合物I。
實施例36(e)係關於實施例32,其中該錠劑含有75至150 mg之化合物I。
實施例36(f)係關於實施例32,其中該錠劑含有75至150 mg之化合物I。
實施例37係關於如實施例32之固態分散體,其中該錠劑懸浮於水或含水溶劑中。
實施例37(a)係關於如本文中所描述之實施例中任一項之固態分散體,其中該固態分散體呈適用於口服劑量之藥囊形式。
實施例37(b)係關於包含如本文中所描述之實施例中任一項之固態分散體的錠劑,其中該錠劑含有150 mg之化合物I。
實施例37(c)係關於實施例37(b),其中該固態分散體為噴霧乾燥分散體。
實施例37(d)係關於實施例37(b)或37(c),其中該錠劑懸浮於視情況含有調味劑之水溶液中。
實施例37(e)係關於實施例37(d),其中該錠劑懸浮於視情況含有調味劑之水中。在此實施例中,調味劑之非限制性實例包括水晶燈。
可用於本發明之固態分散體中的滑動劑之非限制性實例包括膠態二氧化矽、細微粉碎的二氧化矽、矽化微晶纖維素、氧化鎂、聚乙二醇及交聯羧甲纖維素鈉以及其類似物,或其混合物。在一個態樣中,本發明之固態分散體含有膠態二氧化矽作為潤滑劑。所有前述潤滑劑皆為市售可得的。
可用於本發明之固態分散體中的填充劑/黏合劑之非限制性實例包括微晶纖維素、甘露糖醇、山梨糖醇、麥芽糊精、麥芽糖、糊精、二水合磷酸氫鈣、無水磷酸氫鈣、部分預糊化澱粉及磷酸三鈣以及其類似物,或其混合物。在某些實施例中,本發明之固態分散體含有微晶纖維素及甘露糖醇兩者作為填充劑/黏合劑。所有前述賦形劑皆為市售可得的。
可用於本發明之固態分散體中的崩解劑之非限制性實例包括碳酸氫鈉、羥基乙酸澱粉鈉、交聯羧甲纖維素鈉、交聯普維酮及其類似物,或其混合物。在其他實施例中,本發明之固態分散體含有碳酸氫鈉、交聯羧甲纖維素鈉及交聯普維酮作為崩解劑。在其他實施例中,本發明之固態分散體含有交聯羧甲纖維素鈉作為崩解劑。所有前述崩解劑皆為市售可得的。
可用於本發明之固態分散體中的潤滑劑之非限制性實例包括硬脂酸鎂、硬脂酸、棕櫚酸、硬脂酸鈣、巴西棕櫚蠟、經氫化植物油、礦物油、聚乙二醇、硬脂醯反丁烯二酸鈉及其類似物,或其混合物。在一個態樣中,潤滑劑為硬脂酸鎂或硬脂醯反丁烯二酸鈉。在其他實施例中,本發明之固態分散體含有硬脂醯反丁烯二酸鈉作為潤滑劑。所有前述潤滑劑皆為市售可得的。
可用於本發明之固態分散體中的助溶劑之非限制性實例包括牛膽酸鈉、拉巴索、泊洛沙姆、聚乙二醇、共聚普維酮、Transcutol P、丙二醇、Gelucire 44/14、HCO-60、乙醇、Cremophor EL、Tween 80、2羥丙基-β-環糊精及二甲亞碸。在其他實施例中,本發明之固態分散體含有泊洛沙姆、聚乙二醇、共聚普維酮作為助溶劑。在其他實施例中,本發明之固態分散體含有泊洛沙姆407、聚乙二醇400及共聚普維酮作為助溶劑。所有前述助溶劑皆為市售可得的。
在另一實施例中,用於本發明之固態分散體中之助溶劑包括泊洛沙姆。泊洛沙姆可以不同等級使用。可用等級之實例包括泊洛沙姆(68、88、98、108、124、188、237、338及407)。在另一實施例中,泊洛沙姆為泊洛沙姆407。所有前述泊洛沙姆皆為市售可得的。
在本發明之其他實施例中,化合物I與泊洛沙姆之重量比在約2:3至約3:2範圍內。在本發明之其他實施例中,化合物I與泊洛沙姆之重量比在約3:4至約4:3範圍內。在本發明之其他實施例中,化合物I與泊洛沙姆之重量比在約4:5至約5:4範圍內。在本發明之其他實施例中,化合物I與泊洛沙姆之重量比在約9:10至約10:9範圍內。在本發明之其他實施例中,化合物I與泊洛沙姆之重量比為約1:1。
在本發明之其他實施例中,本文中所描述之組合物中之任一者中的交聯普維酮為Polyplasdone® Ultra、Polyplasdone® Ultra-10,Polyplasdone® XL或Polyplasdone® XL-10。在本發明之其他實施例中,本文中所描述之組合物中之任一種中的交聯普維酮為Polyplasdone® Ultra或Polyplasdone® Ultra-10。
在本發明之其他實施例中,可使用非晶形調配物方法來製造化合物I之固態分散體。本發明之其他實施例係關於藉由本發明中描述之非晶形調配物方法中之任一種製造的固態分散體。在某些實施例中,可使用熱熔擠出(HME)製程來調配化合物I之非晶形固態分散體調配物。在其他實施例中,可使用噴霧乾燥分散製程來調配化合物I之非晶形固態分散體調配物。在其他實施例中,化合物I之非晶形固態分散體調配物可為囊狀或錠劑的。在其他實施例中,化合物I之非晶形固態分散體調配物可為囊狀的。在其他實施例中,化合物I之非晶形固態分散體調配物可為錠劑的。
製造化合物 I 之固態分散體的方法
藉由熱熔擠出製造之非晶形化合物 I 的固態分散體
製造化合物 I 之固態分散體的方法
藉由熱熔擠出製造之非晶形化合物 I 的固態分散體
非晶形化合物I之固態分散體可使用熱熔擠出製程來調配(在本文中被稱作調配、HME固態分散體調配或HME調配),其包含熱熔擠出、研磨、摻合,且視情況包含製錠。可組合多個熱熔擠出及研磨批次以用於摻合及製錠,從而使得分批量較大。
用於製造固態分散體之材料之量在本發明中描述之實施例中之任一者中之重量百分比或比率範圍內。
熱熔擠出及研磨
熱熔擠出及研磨
將適量化合物I及一或多種助溶劑(其非限制性實例為,諸如共聚普維酮)添加至摻合器且摻合約5分鐘。可使用之摻合/混合設備之非限制性實例包括擴散混合器(例如,V-摻合器或箱式摻合器)或對流混合器(例如,立式高強度混合器)。在另一實施例中,使用V-摻合器來進行摻合/混合。隨後對內容物進行篩分且隨後轉移回至摻合器且摻合約10分鐘。
在適合容器中對適量之一或多種助溶劑(諸如聚乙二醇400 (PEG400))稱重。使用額外約20 g之PEG 400來設定擠出機,且此額外約20 g之PEG 400並非固態分散體之部分。使用適當設定點且使用約20 g之PEG 400來設定擠出機以調整流動速率。
將摻合物添加至進料斗,且開始擠出製程。根據需要調整且監測擠出參數。收集所得粒化擠出物,且可對其稱重且置放於適合容器中。
摻 合
摻 合
依本發明描述之量添加以下材料至經研磨擠出物中。首先稱取以下賦形劑,及篩選/研磨,隨後添加至經研磨擠出物中:一或多種滑動劑,其非限制性實例為諸如膠態二氧化矽;一或多種崩解劑,其非限制性實例為諸如交聯羧甲纖維素鈉、交聯普維酮及碳酸氫鈉;一或多種填充劑/黏合劑,其非限制性實例為諸如甘露糖醇及微晶纖維素;一或多種助溶劑,其非限制性實例為諸如泊洛沙姆407;一或多種滲透原,其非限制性實例為諸如氯化鈉;及一或多種界面活性劑,其非限制性實例為諸如月桂基硫酸鈉。將經研磨擠出物及經篩選賦形劑添加至摻合器(諸如,箱式摻合器),且進行摻合。
隨後向摻合器添加潤滑劑,諸如硬脂酸鎂,隨後進行摻合。可先稱取潤滑劑及過篩後,加至摻合器中。
接著將摻合物轉移至用於製錠之旋轉式製錠機料斗中,對摻合物製錠。製錠機可經設定以得到目標錠劑重量、硬度及脆度。可監測錠劑摻合物之錠劑重量及硬度。
藉由噴霧乾燥分散法製造非晶形化合物 I 的固態分散體
藉由噴霧乾燥分散法製造非晶形化合物 I 的固態分散體
用於製造固態分散體之材料之量係在本發明所描述任一實施例中之重量百分比或比率範圍內。
稱取噴霧溶液溶劑(其非限制性實例為諸如丙酮及水);HMPCAS;一或多種界面活性劑;及化合物I,置入合適容器中。將界面活性劑緩慢添加至步驟1之噴霧溶液中同時混合,接著添加化合物I,且繼續混合。在混合期間,緩慢添加HMPCAS且繼續混合。使用標準醫藥級噴霧乾燥器(諸如,MS-150)對所得溶液進行噴霧乾燥。在完成噴霧乾燥之後,在烘箱中乾燥該噴霧乾燥分散體(SDD),直至殘餘丙酮低於ICH準則,5000 ppm。隨後將經乾燥SDD轉移至具有除濕劑之適當容器中以免受潮。在揭示內容中,如在犬體內所顯示,已測試此SDD具有藥理學活性。此SDD可進一步藉由乾式粒化及摻合法調配,如下文所描述。
藉由顆粒內及顆粒外賦形劑對噴霧乾燥分散體進行乾式粒化及摻合
藉由顆粒內及顆粒外賦形劑對噴霧乾燥分散體進行乾式粒化及摻合
可將經乾燥SDD及顆粒內賦形劑分配至適當容器中。所採用之顆粒內賦形劑為一或多種潤滑劑(其非限制性實例為諸如硬脂醯反丁烯二酸鈉);一或多種滑動劑(其非限制性實例為諸如膠態二氧化矽);一或多種崩解劑(其非限制性實例為諸如交聯羧甲纖維素鈉);及一或多種填充劑/黏合劑(其非限制性實例為諸如甘露糖醇及微晶纖維素)。將SDD及顆粒內賦形劑添加至適當大小之摻合器且進行摻合。將摻合物過篩(諸如古密爾(comil))以改良摻合均一性且移除大顆粒。進一步摻合此摻合物且隨後排出至適當容器中。
隨後對摻合物進行乾式粒化以使用適當輥壓機(諸如TFC-220輥壓機或其他)且藉由使用所選擇之製程參數(輥類型、RPM及輥壓力)產生條帶。研磨所得條帶(例如,此可藉由使用古密爾來進行)以產生自由流動的粒化。
隨後添加適量顆粒外賦形劑。額外顆粒狀賦形劑包括一或多種潤滑劑(其非限制性實例為諸如硬脂醯反丁烯二酸鈉);一或多種滑動劑(其非限制性實例為諸如膠態二氧化矽及交聯羧甲纖維素鈉);用以粒化及摻合以獲得錠劑壓縮之摻合物。
可接著對經粒化SDD製錠及封裝,如下文所描述。
製錠
製錠
經粒化SDD可藉由旋轉式製錠機製錠。製錠機經設定以得到目標錠劑重量、硬度及脆度。可在初始開始時且以約15分鐘間隔監測重量及硬度。可對錠劑執行金屬檢查及重量排序。
在一個實施例中,製備本發明之組合物的方法包含將化合物I或其醫藥學上可接受之鹽與助溶劑混合。可用於製備本發明之組合物的混合裝備之非限制性實例包括擴散混合器(例如,V-摻合器或箱式摻合器)或對流混合器(例如,立式高強度混合器)。本發明之另一實施例係關於藉由此方法製備之組合物。
在其他實施例中,本發明之組合物包含化合物I之固態分散體及載劑。如本文中所使用,術語「載劑」意謂包括脂質體及奈米顆粒(諸如天然配備之奈米載劑,例如胞外體)及其類似物。眾所周知,胞外體可為高度有效藥物載劑,且存在可將藥物裝載至胞外體中之多種方式,包括描述於J Control Release. 2015年12月10日;219:396-405中之彼等技術,其內容以全文引用之方式併入本文中。
治療方法
治療方法
在一些實施例中,本發明提供一種藉由向有需要之受試者投與治療有效量的本文中所描述之化合物I之固態分散體中之任一種來治療該受試者之疾病或病狀的方法。
在一些實施例中,本發明提供一種治療具有BRAF突變相關之疾病或病狀之受試者的方法,其包含投與本發明之化合物I之固態分散體。在其他實施例中,BRAF突變相關之疾病或病狀為BRAF V600突變相關之疾病或病狀。BRAF V600突變之非限制性實例包括V600E、V600K、V600A、V600G、V600M及V600R。在其他實施例中,BRAF突變相關之疾病或病狀為BRAF V600E突變相關之疾病或病狀。
BRAF V600E突變存在於所有黑色素瘤之約一半(Rajagopalan 2002年)及多種其他癌症以及其他類型之疾病或病狀中。對於本文中所描述之方法及化合物I之用途,涵蓋以下BRAF V600E突變相關之疾病或病狀。
BRAF V600突變相關之疾病或病狀之非限制性實例包括黑色素瘤(包括轉移性黑色素瘤、3A期黑色素瘤、3B期黑色素瘤、3C期黑色素瘤及皮膚著色黑色素瘤)、結腸直腸癌(包括結腸直腸腺癌) (Cohen 2003年)、乳頭狀甲狀腺癌(Fukushima 2003年;Kimura 2003年;Xu 2003年)、多形性甲狀腺癌(Xu 2003年)、漿液性卵巢癌(Nikiforova 2003年)、非小細胞肺癌(Singer 2003年)、胃癌(Brose 2002年)、膽管癌(Lee 2003年)、巴雷特氏食道癌(Barrett's esophageal cancer) (Tannapfel 2003年)及頭頸癌(Sommerer 2004年;Weber 2003年)。BRAF V600突變相關之癌症的其他非限制性實例包括肝細胞癌(Colombino 2012年)、蘭格漢氏細胞組織細胞增多病(Badalian-Very 2010年)、胃腸道基質細胞腫瘤(Agaram 2008年)、多發性骨髓瘤(Chapman 2011年)、小兒星形細胞瘤(其主要包含BRAF重複) (Jones 2008年;Pfister 2008年;Sievert 2009年)、多形性黃星形細胞瘤(Dias-Santagata 2011年;Schindler 2011年)、慢性骨髓性白血病、急性骨髓單核細胞性白血病、雙表型B骨髓單核細胞性白血病、急性骨髓性白血病及毛細胞白血病(Tiacci 2011年)。BRAF V600突變相關之癌症的其他非限制性實例包括周邊神經鞘腫瘤,諸如良性及惡性周邊神經鞘腫瘤(Serrano 2013年)。BRAF V600突變在痣中亦極頻繁(Pollock 2003年),其一般為源自黑色素細胞之發育不良病變且為靜止且因此良性的。BRAF V600突變亦存在於埃德海姆-切斯特病(Erdheim-Chester disease)中。
其他BRAF 600V相關之病狀或病症包括發炎及自體免疫疾病(諸如類風濕性關節炎) (Mol Immunol. 2013年十月;55(3-4):247-52)、腱鞘巨細胞瘤、色素沉著絨毛結節性滑膜炎、肌腱鞘巨細胞瘤、骨巨細胞瘤、子宮頸癌(Gynecol Oncol. 2007年6月;105(3):662-6.)、子宮內膜癌(Fam Cancer. 2014年3月;13(1):1-12)、生殖細胞腫瘤(J Clin Oncol. 2009年5月1日;27(13):2129-36)、前列腺癌(Genes Chromosomes Cancer. 2012年11月;51(11):1014-23)、膀胱癌(Mol Cancer Res. 2015年3月12日. pii: molcanres.0689.2014)、肌周細胞瘤(J Natl Cancer Inst. 2014年7月25日;106(8))、後腎腺瘤(Am J Surg Pathol. 2015年4月;39(4):549-57)、胰腺贅瘤(J Pathol. 2014年3月;232(4):428-35)、神經內分泌腫瘤(Am J Clin Pathol. 2005年2月;123(2):256-60)、內分泌腫瘤(Endocr Relat Cancer. 2004年12月;11(4):855-60)、腎上腺腫瘤(Endocr Relat Cancer. 2009年6月;16(2):565-72)、腎上腺髓質腫瘤、腮腺囊腺癌(Springerplus. 2013年12月18日;2:679. doi: 10.1186/2193-1801-2-679)、多形性膠質母細胞瘤(World J Surg Oncol. 2015年3月11日;13:100)、包括膽管腺瘤之膽管癌(Hepatology. 2015年1月;61(1):403-5)、膽管瘤、B細胞慢性淋巴增生病症(Blood. 2012年1月5日;119(1):188-91)、樹突狀細胞肉瘤(Ann Diagn Pathol. 2015年6月;19(3):113-6)、組織細胞肉瘤及淋巴瘤(例如里赫特氏症候群(Richter's syndrome)、非霍奇金氏淋巴瘤(non-hodgkin's lymphoma)) (Cell. 2015年4月9日;161(2):319-32)。
本發明之實施例38係關於一種治療BRAF突變相關之疾病或病狀的方法,其包含向有需要之受試者投與治療有效量的根據任何實施例1至37之固態分散體,包括本文中所描述之其任何子實施例,其中該BRAF突變相關之疾病或病狀為黑色素瘤、結腸直腸癌、乳頭狀甲狀腺癌、乳頭狀顱咽管瘤、多形性甲狀腺癌、卵巢癌、非小細胞肺癌、胃癌、膽管癌、巴雷特氏食道癌、頭頸癌、肝細胞癌、乳癌、蘭格漢氏細胞組織細胞增多病、胃腸道基質細胞腫瘤(GIST)、多發性骨髓瘤、小兒星形細胞瘤、多形性黃星形細胞瘤、慢性骨髓性白血病、急性骨髓單核細胞性白血病、雙表型B骨髓單核細胞性白血病、急性骨髓性白血病、毛細胞白血病、痣、埃德海姆-切斯特病、惡性周邊神經鞘腫瘤、發炎及自體免疫疾病、腱鞘巨細胞瘤、色素沉著絨毛結節性滑膜炎、肌腱鞘巨細胞瘤、骨巨細胞瘤、子宮頸癌、子宮內膜癌、生殖細胞腫瘤、前列腺癌、膀胱癌、肌周細胞瘤、後腎腺瘤、胰腺贅瘤、神經內分泌腫瘤、內分泌腫瘤、腎上腺腫瘤、腎上腺髓質腫瘤、腮腺囊腺癌、多形性膠質母細胞瘤、包括膽管腺瘤之膽管癌、B細胞慢性淋巴增生病症、樹突狀細胞肉瘤、組織細胞肉瘤或淋巴瘤。
本發明之實施例38(a)係關於實施例38,其中該BRAF突變相關之疾病或病狀為埃德海姆-切斯特病。
本發明之實施例38(b)係關於實施例38,其中該BRAF突變相關之疾病或病狀為黑色素瘤。
本發明之實施例38(c)係關於實施例38,其中該BRAF突變相關之疾病或病狀為轉移性黑色素瘤。
本發明之實施例38(d)係關於實施例38,其中該BRAF突變相關之疾病或病狀為結腸直腸癌。
本發明之實施例38(e)係關於實施例38,其中該BRAF突變相關之疾病或病狀為乳頭狀甲狀腺癌。
本發明之實施例38(f)係關於實施例38,其中該BRAF突變相關之疾病或病狀為乳頭狀顱咽管瘤。
本發明之實施例38(g)係關於實施例38,其中該BRAF突變相關之疾病或病狀為卵巢癌。
本發明之實施例38(h)係關於實施例38,其中該BRAF突變相關之疾病或病狀為多形性甲狀腺癌。
本發明之實施例38(i)係關於實施例38,其中該BRAF突變相關之疾病或病狀為非小細胞肺癌。
本發明之實施例38(j)係關於實施例38,其中該BRAF突變相關之疾病或病狀為胃癌。
本發明之實施例38(k)係關於實施例38,其中該BRAF突變相關之疾病或病狀為蘭格漢氏細胞組織細胞增多病。
本發明之實施例38(l)係關於實施例38,其中該BRAF突變相關之疾病或病狀為小兒星形細胞瘤。
本發明之實施例38(m)係關於實施例38,其中該BRAF突變相關之疾病或病狀為神經膠母細胞瘤。
本發明之實施例38(n)係關於實施例38,其中該BRAF突變相關之疾病或病狀為多發性骨髓瘤。
本發明之實施例38(o)係關於實施例38,其中該BRAF突變相關之疾病或病狀為前列腺癌。
本發明之實施例38(p)係關於實施例38,其中該BRAF突變相關之疾病或病狀為膀胱癌。
本發明之實施例38(q)係關於實施例38,其中該BRAF突變相關之疾病或病狀為GIST、胃癌或巴雷特氏食道癌。
本發明之實施例38(r)係關於實施例38,其中該BRAF突變相關之疾病或病狀為頭頸癌。
本發明之實施例39係關於如實施例38之方法,其中該BRAF突變相關之疾病或病狀為肝細胞癌、蘭格漢氏細胞組織細胞增多病、埃德海姆-切斯特病、胃腸道基質細胞腫瘤、毛細胞白血病、黑色素瘤、結腸直腸癌、乳頭狀甲狀腺癌、多形性甲狀腺癌、卵巢癌、非小細胞肺癌、結腸直腸癌、多形性膠質母細胞瘤、前列腺癌、胃癌、膽管癌或巴雷特氏食道癌。
組合療法
組合療法
在一些實施例中,本發明提供治療有需要之動物受試者中之本文中所描述之疾病或病狀中之任一種的方法,其中該方法涉及與該疾病或病狀之一或多個其他療法組合地向受試者投與本發明之化合物I之有效量的固態分散體。
A. 與另一藥劑組合之化合物 I
A. 與另一藥劑組合之化合物 I
在另一態樣中,本發明提供一種藉由向有需要之受試者投與本發明之化合物I之有效量的固態分散體來治療該受試者之癌症的方法,該等固態分散體具有一或多種適合化學治療劑。在一個實施例中,一或多種適合化學治療劑係選自:烷化劑,其包括但不限於阿多來新(adozelesin)、六甲蜜胺(altretamine)、苯達莫司汀(bendamustine)、比折來新(bizelesin)、白消安(busulfan)、卡鉑(carboplatin)、卡波醌(carboquone)、卡莫氟(carmofur)、卡莫司汀(carmustine)、氯芥苯丁酸(chlorambucil)、順鉑(cisplatin)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、雌莫司汀(estramustine)、依託格魯(etoglucid)、福莫司汀(fotemustine)、海普法姆(hepsulfam)、異環磷醯胺(ifosfamide)、英丙舒凡(improsulfan)、伊洛福芬(irofulven)、洛莫司汀(lomustine)、甘露舒凡(mannosulfan)、氮芥(mechlorethamine)、美法侖(melphalan)、二溴甘露醇(mitobronitol)、奈達鉑(nedaplatin)、尼莫司汀(nimustine)、奧沙利鉑(oxaliplatin)、哌泊舒凡(piposulfan)、潑尼氮芥(prednimustine)、丙卡巴肼(procarbazine)、雷莫司汀(ranimustine)、賽特鉑(satraplatin)、司莫司汀(semustine)、鏈脲菌素(streptozocin)、替莫唑胺(temozolomide)、噻替派(thiotepa)、曲奧舒凡(treosulfan)、三亞胺醌(triaziquone)、曲他胺(triethylenemelamine)、四硝酸三鉑(triplatin tetranitrate)、曲磷胺(trofosphamide)及烏拉莫司汀(uramustine);抗生素,其包括但不限於阿克拉黴素(aclarubicin)、胺柔比星(amrubicin)、博萊黴素(bleomycin)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、阿黴素(doxorubicin)、依沙蘆星(elsamitrucin)、表柔比星(epirubicin)、艾達黴素(idarubicin)、美諾立爾(menogaril)、絲裂黴素(mitomycin)、新抑癌蛋白(neocarzinostatin)、噴司他丁(pentostatin)、吡柔比星(pirarubicin)、普卡黴素(plicamycin)、伐柔比星(valrubicin)及佐柔比星(zorubicin);抗代謝產物,其包括但不限於胺基喋呤(aminopterin)、阿紮胞苷(azacitidine)、硫唑嘌呤(azathioprine)、卡培他濱(capecitabine)、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、阿糖胞苷(cytarabine)、地西他濱(decitabine)、氟尿苷(floxuridine)、氟達拉賓(fludarabine)、5-氟尿嘧啶(5-fluorouracil)、吉西他濱(gemcitabine)、羥基尿素(hydroxyurea)、巰基嘌呤(mercaptopurine)、甲胺喋呤(methotrexate)、奈拉濱(nelarabine)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、喃氟啶-尿嘧啶(tegafur-uracil)、硫鳥嘌呤(thioguanine)、甲氧苄啶(trimethoprim)、曲美沙特(trimetrexate)及阿糖腺苷(vidarabine);免疫療法,其包括吲哚胺2,3-二加氧酶(IDO)抑制劑;抗體療法,其包括但不限於免疫檢查點抑制劑,諸如PD-1抑制劑(諸如帕博利珠單抗(pembrolizumab)、納武單抗(nivolumab)、皮立珠單抗(pidilizumab))或PD-L1抑制劑(諸如BMS-936559、MEDI4736、MPDL3280A或MSB0010718C)、阿侖單抗(alemtuzumab)、貝伐單抗(bevacizumab)、西妥昔單抗(cetuximab)、加利昔單抗(galiximab)、吉妥單抗(gemtuzumab)、帕尼單抗(panitumumab)、帕妥珠單抗(pertuzumab)、利妥昔單抗(rituximab)、貝倫妥單抗(brentuximab)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、90 Y替伊莫單抗(90 Y ibritumomab tiuxetan)、伊派利單抗(ipilimumab)、曲美單抗(tremelimumab)及抗CTLA-4抗體;荷爾蒙或荷爾蒙拮抗劑,其包括但不限於阿那曲唑(anastrozole)、雄激素、布舍瑞林(buserelin)、己烯雌酚(diethylstilbestrol)、依西美坦(exemestane)、氟他胺(flutamide)、氟維司群(fulvestrant)、戈舍瑞林(goserelin)、艾多昔芬(idoxifene)、來曲唑(letrozole)、亮丙立德(leuprolide)、甲地孕酮(magestrol)、雷諾昔芬(raloxifene)、他莫昔芬(tamoxifen)及托瑞米芬(toremifene);紫杉烷,其包括但不限於DJ-927、多西他賽(docetaxel)、TPI 287、拉洛他賽(larotaxel)、奧他賽(ortataxel)、太平洋紫杉醇(paclitaxel)、DHA-太平洋紫杉醇及替司他賽(tesetaxel);類視黃素,其包括但不限於亞利崔托寜(alitretinoin)、貝瑟羅汀(bexarotene)、非瑞替尼(fenretinide)、異維甲酸(isotretinoin)及維甲酸(tretinoin;);生物鹼,其包括但不限於地美可辛(demecolcine)、高粗榧鹼(homoharringtonine)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)及長春瑞賓(vinorelbine);抗血管生成劑,其包括但不限於AE-941 (GW786034、新伐司他(Neovastat))、ABT-510、2-甲氧雌二醇、來那度胺(lenalidomide)及撒利多胺(thalidomide);拓樸異構酶抑制劑,其包括但不限於安吖啶(amsacrine)、貝洛替康(belotecan)、艾特咔林(edotecarin)、依託泊苷(etoposide)、磷酸依託泊苷(etoposide phosphate)、依喜替康(exatecan)、伊立替康(irinotecan) (以及活性代謝物SN-38 (7-乙基-10-羥基-喜樹鹼))、胺甲硫蒽酮(lucanthone)、米托蒽醌(mitoxantrone)、匹蒽醌(pixantrone)、盧比替康(rubitecan)、替尼泊甙(teniposide)、拓朴替康(topotecan)及9-胺基喜樹鹼(9-aminocamptothecin);激酶抑制劑,其包括但不限於阿西替尼(axitinib) (AG 013736)、達沙替尼(dasatinib) (BMS 354825)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、夫拉平度(flavopiridol)、甲磺酸伊馬替尼(imatinib mesylate)、卡博替尼(cabozantinib)、拉帕替尼(lapatinib)、二磷酸莫替沙尼(motesanib diphosphate) (AMG 706)、尼羅替尼(nilotinib) (AMN107)、塞利希布(seliciclib)、索拉非尼(sorafenib)、蘋果酸舒尼替尼(sunitinib malate)、AEE-788、BMS-599626、UCN-01 (7-羥基星孢菌素(7-hydroxystaurosporine))、維羅非尼(vemurafenib)、達拉非尼(dabrafenib)、司美替尼(selumetinib)及凡塔藍尼(vatalanib);靶向信號轉導抑制劑,其包括但不限於硼替佐米(bortezomib)、格爾德黴素(geldanamycin)及雷帕黴素(rapamycin);生物反應調節劑,其包括但不限於咪喹莫特(imiquimod)、干擾素-γ及介白素-2;及其他化學治療劑,其包括但不限於3-AP (3-胺基-2-羥基醛硫半卡巴肼(3-amino-2-carboxyaldehyde thiosemicarbazone))、阿曲生坦(altrasentan)、胺麩精(aminoglutethimide)、阿那格雷(anagrelide)、天冬醯胺酶(asparaginase)、苔蘚蟲素-1 (bryostatin-1)、西侖吉肽(cilengitide)、艾利莫耳(elesclomol)、甲磺酸艾日布林(eribulin mesylate) (E7389)、伊沙匹隆(ixabepilone)、氯尼達明(lonidamine)、馬索羅酚(masoprocol)、米托瓜宗(mitoguanazone)、奧利默森(oblimersen)、舒林酸(sulindac)、睪內酯(testolactone)、噻唑呋林(tiazofurin)、mTOR抑制劑(例如,INK28、AZD8055、西羅莫司(sirolimus)、坦羅莫司(temsirolimus)、依維莫司(everolimus)、德佛利姆(deforolimus)))、PI3K抑制劑(例如,BEZ235、GDC-0941、XL147、XL765)、Cdk4抑制劑(例如,PD-332991)、AKt抑制劑、Hsp90抑制劑(例如,格爾德黴素(geldanamycin)、根赤殼菌素(radicicol)、坦螺旋黴素(tanespimycin))、法呢基轉移酶抑制劑(例如,替吡法尼(tipifarnib))及芳香酶抑制劑(阿那曲唑來曲唑依西美坦(anastrozole letrozole exemestane))。在本文中所描述之方法及用途之另一實施例中,本文中所描述之固態分散體與選自以下各者之化學治療劑組合投與:卡培他濱(capecitabine)、5-氟尿嘧啶(5-fluorouracil)、卡鉑(carboplatin)、達卡巴嗪(dacarbazine)、吉非替尼(gefitinib)、奧沙利鉑(oxaliplatin)、太平洋紫杉醇(paclitaxel)、SN-38、替莫唑胺(temozolomide)、長春鹼(vinblastine)、貝伐單抗(bevacizumab)、西妥昔單抗(cetuximab)、干擾素-α、介白素2或埃羅替尼(erlotinib)。在另一實施例中,化學治療劑為MeK抑制劑。例示性Mek抑制劑包括但不限於曲美替尼、考比替尼、AS703026、AZD6244 (司美替尼(Selumetinib))、AZD8330、BIX 02188、CI-1040 (PD184352)、GSK1120212 (JTP-74057)、PD0325901、PD318088、PD98059、RDEA119 (BAY 869766)、TAK-733及U0126-EtOH。在另一實施例中,化學治療劑為酪胺酸激酶抑制劑。例示性酪胺酸激酶抑制劑包括(但不限於) AEE788、AG-1478 (酪胺酸磷酸化抑制劑(Tyrphostin) AG-1478)、AG-490、阿帕替尼(Apatinib) (YN968D1)、AV-412、AV-951(替沃紮尼(Tivozanib))、阿西替尼(Axitinib)、AZD8931、BIBF1120 (瓦格特氟(Vargatef))、BIBW2992 (阿法替尼(Afatinib))、BMS794833、BMS-599626、布立尼布(Brivanib) (BMS-540215)、丙胺酸布立尼布(Brivanib alaninate) (BMS-582664)、西地尼布(Cediranib) (AZD2171)、大黃根酸(大黃酚)、克諾拉尼(Crenolanib) (CP-868569)、CUDC-101、CYC116、二乳酸多韋替尼(Dovitinib Dilactic acid) (二乳酸TKI258)、E7080、鹽酸埃羅替尼(Erlotinib Hydrochloride) (特羅凱(Tarceva)、CP-358774、OSI-774、NSC-718781)、弗雷替尼(Foretinib) (GSK1363089、XL880)、吉非替尼(Gefitinib) (ZD-1839或易瑞沙(Iressa))、伊馬替尼(Imatinib) (格列維克(Gleevec))、甲磺酸伊馬替尼(Imatinib Mesylate)、Ki8751、KRN 633、拉帕替尼(Lapatinib) (泰克泊(Tykerb))、立尼法尼(Linifanib) (ABT-869)、馬賽替尼(Masitinib) (馬賽韋特(Masivet)、AB1010)、MGCD-265、莫替沙尼(Motesanib) (AMG-706)、MP-470、木利替尼(Mubritinib) (TAK 165)、來那替尼(Neratinib) (HKI-272)、NVP-BHG712、OSI-420 (去甲基埃羅替尼(Desmethyl Erlotinib)、CP-473420)、OSI-930、帕唑帕尼HCl (Pazopanib HCl)、PD-153035 HCl、PD173074、培利替尼(Pelitinib) (EKB-569)、PF299804、普納替尼(Ponatinib) (AP24534)、PP121、RAF265 (CHIR-265)、Raf265衍生物、瑞戈非尼(Regorafenib) (BAY 73-4506)、甲苯磺酸索拉非尼(Sorafenib Tosylate) (雷沙瓦(Nexavar))、蘋果酸舒尼替尼(Sunitinib Malate) (舒癌特(Sutent))、替拉替尼(Telatinib) (BAY 57-9352)、TSU-68 (SU6668)、凡德他尼(Vandetanib) (紮克替馬(Zactima))、二鹽酸凡塔藍尼(Vatalanib dihydrochloride) (PTK787)、WZ3146、WZ4002、WZ8040、卡博替尼(Cabozantinib)、XL647、EGFR siRNA、FLT4 siRNA、KDR siRNA、抗糖尿病劑(諸如二甲雙胍(metformin))、PPAR促效劑(羅格列酮(rosiglitazone)、吡格列酮(pioglitazone)、苯紮貝特(bezafibrate)、環丙貝特(ciprofibrate)、氯貝特(clofibrate)、吉非羅齊(gemfibrozil)、非諾貝特(fenofibrate)、英迪列紮(indeglitazar))及DPP4抑制劑(西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、多格列汀(dutogliptin)、吉格列汀(gemigliptin)、阿格列汀(alogliptin))。在另一實施例中,藥劑為BET抑制劑(諸如BRD2、BRD3、BRD4及/或BRDT)。在另一實施例中,藥劑為EGFR抑制劑。例示性EGFR抑制劑包括但不限於AEE-788、AP-26113、BIBW-2992 (特沃克(Tovok))、CI-1033、GW-572016、易瑞沙(Iressa)、LY2874455、RO-5323441、特羅凱(Tarceva) (埃羅替尼(Erlotinib)、OSI-774)、CUDC-101、西妥昔單抗(cetuximab)及WZ4002。在另一實施例中,本發明提供一種藉由向有需要之受試者投與本文中所描述之有效量的固態分散體來治療該受試者之癌症的方法,該等固態分散體具有拓樸異構酶抑制劑(諸如伊立替康)及EGFR抑制劑(諸如西妥昔單抗)。在另一實施例中,本發明提供一種藉由向有需要之受試者投與本文中所描述之有效量的固態分散體來治療該受試者之癌症的方法,該等固態分散體具有G蛋白偶聯雌激素受體(GPER)促效劑。
在其他實施例中,本發明之治療BRAF突變相關之疾病或病狀的方法進一步包含與CYP抑制劑共同投與以改良化合物I對所治療之受試者之曝露及功效。
本發明之實施例40係關於如實施例38、38(a)至34(r)及39中任一項之方法,其進一步包含向該受試者共同投與CYP抑制劑。
本發明之實施例40(a)係關於實施例36,其中該固態分散體及該CYP抑制劑係依序投與。
本發明之實施例41係關於如實施例36之方法,其中該CYP抑制劑為CYP3A抑制劑。
本發明之實施例42係關於如實施例41之方法,其中該CYP3A抑制劑為波普瑞韋(boceprevir)、考比西他(cobicistat)、考尼伐坦(conivaptan)、丹諾普韋(danoprevir)、利托那韋(ritonavir)、埃替格韋(elvitegravir)、利托那韋(ritonavir)、葡萄柚汁、茚地那韋(indinavir)、利托那韋(ritonavir)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、洛匹那韋(lopinavir)、利托那韋(ritonavir)、帕瑞普韋和(paritaprevir)、利托那韋(ritonavir)、奧比他韋(ombitasvir)、達薩布韋(dasabuvir)、泊沙康唑(posaconazole)、利托那韋(ritonavir)、沙奎那韋(saquinavir)、利托那韋(ritonavir)、特拉匹韋(telaprevir)、替拉那韋(tipranavir)、利托那韋(ritonavir)、醋竹桃黴素(troleandomycin)、伏立康唑(voriconazole)、克拉黴素(clarithromycin)、地爾硫卓(diltiazem)、艾德斯布(idelalisib)、奈法唑酮(nefazodone)、奈非那韋(nelfinavir),或其組合。
本發明之實施例42(a)係關於如實施例41之方法,其中該CYP3A抑制劑為波普瑞韋(boceprevir)、考比西他(cobicistat)、考尼伐坦(conivaptan)、丹諾普韋(danoprevir)及利托那韋(ritonavir)、埃替格韋(elvitegravir)及利托那韋(ritonavir)、葡萄柚汁、茚地那韋(indinavir)及利托那韋(ritonavir)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、洛匹那韋(lopinavir)及利托那韋(ritonavir)、泊沙康唑(posaconazole)、利托那韋(ritonavir)、沙奎那韋(saquinavir)及利托那韋(ritonavir)、特拉匹韋(telaprevir)、替拉那韋(tipranavir)及利托那韋(ritonavir)、醋竹桃黴素(troleandomycin)、伏立康唑(voriconazole)、克拉黴素(clarithromycin)、地爾硫卓(diltiazem)、艾德斯布(idelalisib)、奈法唑酮(nefazodone)、奈非那韋(nelfinavir)或帕瑞普韋和(paritaprevir)及利托那韋(ritonavir)及奧比他韋(ombitasvir)及/或達薩布韋(dasabuvir)。
本發明之實施例43係關於如實施例42之方法,其中該CYP3A抑制劑為考比西他。
B. 與 另一 療法 組合之化合物 I 之固態分散體
B. 與 另一 療法 組合之化合物 I 之固態分散體
在一些實施例中,本發明提供一種藉由與治療癌症方面有效之一或多個其他療法或醫學程序組合地向有需要之受試者投與化合物I之有效量的固態分散體來治療該受試者之癌症的方法。其他療法或醫學程序包括適合抗癌療法(例如,藥物療法、疫苗療法、基因療法、光動力療法)或醫學程序(例如,手術、輻射治療、高溫加熱、骨髓或幹細胞移植)。在一個實施例中,一或多種適合抗癌療法或醫學程序係選自以下各者:使用化學治療劑(例如化學治療藥物)之治療、輻射治療(例如x射線、γ射線或電子、質子、中子或α粒子束)、高溫加熱(例如微波、超音波、射頻切除)、疫苗療法(例如AFP基因肝細胞癌疫苗、AFP腺病毒載體疫苗、AG-858、同種異體GM-CSF分泌乳癌疫苗、樹突狀細胞肽疫苗)、基因療法(例如Ad5CMV-p53載體、編碼MDA7之腺病毒載體、腺病毒5-腫瘤壞死因子α)、光動力療法(例如胺基乙醯丙酸、莫特沙芬鎦)、溶瘤病毒或細菌療法、手術或骨髓及幹細胞移植。在某些實施例中,本發明提供一種藉由向有需要之受試者投與本文中所描述之化合物I之固態分散體之有效量的化合物且分開或同時應用如本文中所描述之輻射治療來治療該受試者之癌症的方法。在一個實施例中,本發明提供一種藉由向有需要之受試者投與本文中所描述之化合物I之有效量的固態分散體之有效量繼而進行輻射治療(例如,x射線、γ射線或電子、質子、中子或α粒子束)來治療該受試者之癌症的方法。在另一實施例中,本發明提供一種藉由進行輻射治療(例如,x射線、γ射線或電子、質子、中子或α粒子束)繼而向有需要之受試者投與本文中所描述之化合物I之有效量的固態分散體之有效量來治療該受試者之癌症的方法。在又一實施例中,本發明提供一種藉由同時向有需要之受試者投與本文中所描述之化合物I之固態分散體及輻射療法(例如,x射線、γ射線或電子、質子、中子或α粒子束)來治療該受試者之癌症的方法。
激酶活性分析
激酶活性分析
可利用數種不同的激酶活性分析來分析活性調節劑及/或測定用於特定激酶或一組激酶之調節劑的特異性,諸如特此以全文引用之方式併入的美國專利公開案第US 2016/0339025 A1號公開案中所描述。一般熟習此項技術者可易於鑑別可利用之其他分析且可修改特定應用之分析。舉例而言,關於激酶之眾多論文描述可使用之分析。
額外替代分析可採用結合測定。舉例而言,此種分析可藉由改變連接至抗生蛋白鏈菌素或磷光體特異性抗體之供體及受體試劑在螢光共振能量轉移(FRET)格式中或使用AlphaScreen (擴增發光近接均質分析(amplified luminescent proximity homogeneous assay))格式經格式化。
如本文中所使用之縮寫具有如下各別含義:
參考文獻
Agaram, N. P.et al. Novel V600EBRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.Genes Chromosomes Cancer 47 , 853-859 (2008).
Anforth RM, Blumetti TCMP, Kefford RF, Sharma R, Scolyer R a, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br. J. Dermatol. 2012 Nov;167(5):1153-1160.
Badalian-Very, G.et al. RecurrentBRAF mutations in Langerhans cell histiocytosis.Blood 116 , 1919-1923 (2010).
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010 Sep 30;467(7315):596-599.
Brose, M. S.et al. BRAF andRAS mutations in human lung cancer and melanoma.Cancer Res. 62 , 6997-7000 (2002).
Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N. Engl. J. Med. 2012 Dec 13;367(24):2316-2321.
Chapman, M. A.et al. Initial genome sequencing and analysis of multiple myeloma.Nature 471 , 467-472 (2011).
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. for BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-2516.
Cohen, Y.et al. BRAF mutation in papillary thyroid carcinoma.J. Natl Cancer Inst. 95 , 625-627 (2003).
Colombino, M.et al. BRAF andPIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy.Cell Death Dis. 3 , e259 (2012).
Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012 Mar;2(3):227-235.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-954.
Dias-Santagata, D.et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications.PLoS ONE 6 , e17948 (2011).
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010 Aug 26;363(9):809-819.
Fukushima, T.et al. BRAF mutations in papillary carcinomas of the thyroid.Oncogene 22 , 6455-6457 (2003).
Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. Nature Publishing Group; 2010 Mar 18;464(7287):431-435.
Hauschild A, Grob J-J, Demidov L V, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. Elsevier Ltd; 2012 Jul 28;380(9839):358-365.
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. Elsevier Ltd; 2010 Jan 22;140(2):209-221.
Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch. Dermatol. 2012 May;148(5):628-633.
Jones, D. T.et al. Tandem duplication producing a novel oncogenicBRAF fusion gene defines the majority of pilocytic astrocytomas.Cancer Res. 68 , 8673-8677 (2008).
Kimura, E. T.et al. High prevalence ofBRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.Cancer Res. 63 , 1454-1457 (2003).
Lacouture ME, Desai a, Soltani K, Petronic-Rosic V, Laumann a E, Ratain MJ, et al. Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin. Exp. Dermatol. 2006 Nov;31(6):783-785.
Lee, S. H.et al. BRAF andKRAS mutations in stomach cancer.Oncogene 22 , 6942-6945 (2003).
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 2010 Dec 16;468(7326):973-977.
Nikiforova, M. N.et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.J. Clin. Endocrinol. Metab. 88 , 5399-5404 (2003).
Oberholzer P a, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J. Clin. Oncol. 2012 Jan 20;30(3):316-321.
Pfister, S.et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.J. Clin. Invest. 118 , 1739-1749 (2008).
Pollock, P. M.et al. High frequency ofBRAF mutations in nevi.Nature Genet. 33 , 19-20 (2003).
Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. Nature Publishing Group; 2011 Dec 15;480(7377):387-390.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. Nature Publishing Group; 2010 Mar 18;464(7287):427-430.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012 Mar 1;483(7387):100-103.
Rajagopalan, H.et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature 418 , 934 (2002).
Robert C, Arnault J-P, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr. Opin. Oncol. 2011 Mar;23(2):177-182.
Schindler, G.et al. Analysis ofBRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.Acta Neuropathol. 121 , 397-405 (2011).
Serrano C,et al . BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours.Histopathology , 2013 Feb; 62(3):499-504.
Sievert, A. J.et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novelBRAF fusion gene.Brain Pathol. 19 , 449-458 (2009).
Singer, G.et al. Mutations inBRAF andKRAS characterize the development of low-grade ovarian serous carcinoma.J. Natl Cancer Inst. 95 , 484-486 (2003).
Sommerer, F.et al. Mutations ofBRAF andKRAS2 in the development of Barrett's adenocarcinoma.Oncogene 23 , 554-558 (2004).
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 2012 Feb 23;366(8):707-714.
Stellwagen JC, Adjabeng GM, Arnone MR, Dickerson SH, Han C, Hornberger KR, et al. Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup. Bioorg. Med. Chem. Lett. Elsevier Ltd; 2011 Aug 1;21(15):4436-4440.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012 487:500-504.
Su, F., Viros, A., Milagre, C., Trunzer, K., Bollag, G., Spleiss, O., Reis-Filho, J. S., et al. (2012). RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. The New England journal of medicine, 366(3), 207-15.
Tannapfel, A.et al. Mutations of theBRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.Gut 52 , 706-712 (2003).
Tiacci, E.et al. BRAF mutations in hairy-cell leukemia.N. Engl. J. Med. 364 , 2305-2315 (2011).
Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., et al. (2008). Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 3041-6.
Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. Elsevier Inc.; 2010 Dec 14;18(6):683-695.
Weber, A.et al. Mutations of theBRAF gene in squamous cell carcinoma of the head and neck.Oncogene 22 , 4757-4759 (2003).
Xu, X., Quiros, R. M., Gattuso, P., Ain, K. B. & Prinz, R. A. High prevalence ofBRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines.Cancer Res. 63 , 4561-4567 (2003).
Zimmer L, Hillen U, Livingstone E, Lacouture ME, Busam K, Carvajal RD, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012 30:2375-2383.
實例
Agaram, N. P.et al. Novel V600EBRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.Genes Chromosomes Cancer 47 , 853-859 (2008).
Anforth RM, Blumetti TCMP, Kefford RF, Sharma R, Scolyer R a, Kossard S, et al. Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma. Br. J. Dermatol. 2012 Nov;167(5):1153-1160.
Badalian-Very, G.et al. RecurrentBRAF mutations in Langerhans cell histiocytosis.Blood 116 , 1919-1923 (2010).
Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010 Sep 30;467(7315):596-599.
Brose, M. S.et al. BRAF andRAS mutations in human lung cancer and melanoma.Cancer Res. 62 , 6997-7000 (2002).
Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N. Engl. J. Med. 2012 Dec 13;367(24):2316-2321.
Chapman, M. A.et al. Initial genome sequencing and analysis of multiple myeloma.Nature 471 , 467-472 (2011).
Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. for BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-2516.
Cohen, Y.et al. BRAF mutation in papillary thyroid carcinoma.J. Natl Cancer Inst. 95 , 625-627 (2003).
Colombino, M.et al. BRAF andPIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy.Cell Death Dis. 3 , e259 (2012).
Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012 Mar;2(3):227-235.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-954.
Dias-Santagata, D.et al. BRAF V600E mutations are common in pleomorphic xanthoastrocytoma: diagnostic and therapeutic implications.PLoS ONE 6 , e17948 (2011).
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010 Aug 26;363(9):809-819.
Fukushima, T.et al. BRAF mutations in papillary carcinomas of the thyroid.Oncogene 22 , 6455-6457 (2003).
Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. Nature Publishing Group; 2010 Mar 18;464(7287):431-435.
Hauschild A, Grob J-J, Demidov L V, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. Elsevier Ltd; 2012 Jul 28;380(9839):358-365.
Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. Elsevier Ltd; 2010 Jan 22;140(2):209-221.
Huang V, Hepper D, Anadkat M, Cornelius L. Cutaneous toxic effects associated with vemurafenib and inhibition of the BRAF pathway. Arch. Dermatol. 2012 May;148(5):628-633.
Jones, D. T.et al. Tandem duplication producing a novel oncogenicBRAF fusion gene defines the majority of pilocytic astrocytomas.Cancer Res. 68 , 8673-8677 (2008).
Kimura, E. T.et al. High prevalence ofBRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.Cancer Res. 63 , 1454-1457 (2003).
Lacouture ME, Desai a, Soltani K, Petronic-Rosic V, Laumann a E, Ratain MJ, et al. Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin. Exp. Dermatol. 2006 Nov;31(6):783-785.
Lee, S. H.et al. BRAF andKRAS mutations in stomach cancer.Oncogene 22 , 6942-6945 (2003).
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature, 2010 Dec 16;468(7326):973-977.
Nikiforova, M. N.et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas.J. Clin. Endocrinol. Metab. 88 , 5399-5404 (2003).
Oberholzer P a, Kee D, Dziunycz P, Sucker A, Kamsukom N, Jones R, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J. Clin. Oncol. 2012 Jan 20;30(3):316-321.
Pfister, S.et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas.J. Clin. Invest. 118 , 1739-1749 (2008).
Pollock, P. M.et al. High frequency ofBRAF mutations in nevi.Nature Genet. 33 , 19-20 (2003).
Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. Nature Publishing Group; 2011 Dec 15;480(7377):387-390.
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. Nature Publishing Group; 2010 Mar 18;464(7287):427-430.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012 Mar 1;483(7387):100-103.
Rajagopalan, H.et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.Nature 418 , 934 (2002).
Robert C, Arnault J-P, Mateus C. RAF inhibition and induction of cutaneous squamous cell carcinoma. Curr. Opin. Oncol. 2011 Mar;23(2):177-182.
Schindler, G.et al. Analysis ofBRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma.Acta Neuropathol. 121 , 397-405 (2011).
Serrano C,et al . BRAF V600E and KRAS G12S mutations in peripheral nerve sheath tumours.Histopathology , 2013 Feb; 62(3):499-504.
Sievert, A. J.et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novelBRAF fusion gene.Brain Pathol. 19 , 449-458 (2009).
Singer, G.et al. Mutations inBRAF andKRAS characterize the development of low-grade ovarian serous carcinoma.J. Natl Cancer Inst. 95 , 484-486 (2003).
Sommerer, F.et al. Mutations ofBRAF andKRAS2 in the development of Barrett's adenocarcinoma.Oncogene 23 , 554-558 (2004).
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 2012 Feb 23;366(8):707-714.
Stellwagen JC, Adjabeng GM, Arnone MR, Dickerson SH, Han C, Hornberger KR, et al. Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup. Bioorg. Med. Chem. Lett. Elsevier Ltd; 2011 Aug 1;21(15):4436-4440.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012 487:500-504.
Su, F., Viros, A., Milagre, C., Trunzer, K., Bollag, G., Spleiss, O., Reis-Filho, J. S., et al. (2012). RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. The New England journal of medicine, 366(3), 207-15.
Tannapfel, A.et al. Mutations of theBRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma.Gut 52 , 706-712 (2003).
Tiacci, E.et al. BRAF mutations in hairy-cell leukemia.N. Engl. J. Med. 364 , 2305-2315 (2011).
Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., et al. (2008). Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 3041-6.
Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. Elsevier Inc.; 2010 Dec 14;18(6):683-695.
Weber, A.et al. Mutations of theBRAF gene in squamous cell carcinoma of the head and neck.Oncogene 22 , 4757-4759 (2003).
Xu, X., Quiros, R. M., Gattuso, P., Ain, K. B. & Prinz, R. A. High prevalence ofBRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines.Cancer Res. 63 , 4561-4567 (2003).
Zimmer L, Hillen U, Livingstone E, Lacouture ME, Busam K, Carvajal RD, et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J Clin Oncol. 2012 30:2375-2383.
實例
下文描述本發明相關之實例。在大多數情況下,可使用替代性技術。該等實例意欲為說明性的且並非限制或限定本發明之範疇。
實例 1 :化合物 I 之合成
實例 1 :化合物 I 之合成
熟習此項技術者亦將認識到,在有機化學中之標準處理程序期間,常常使用酸及鹼。在本發明內所描述之實驗程序期間,有時產生母化合物之鹽,只要其具有所需固有酸性或鹼性。此外,化合物使用標準方法(諸如質譜法、核磁共振(NMR)、光譜法等)表徵。1
H核磁共振(NMR)光譜法使用在300 MHz下操作之光譜儀進行。
步驟 1 . 製備 ( 5 - 溴基 - 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 )-( 2 , 6 - 二氟 - 3 - 硝基 - 苯基 ) 甲酮 ( 3 )
步驟 1 . 製備 ( 5 - 溴基 - 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 )-( 2 , 6 - 二氟 - 3 - 硝基 - 苯基 ) 甲酮 ( 3 )
向50公升燒瓶中依序添加1,2-二氯乙烷(DCE,20 L)及5-溴氮雜吲哚(1
) (2 kg,10.152 mol),得到橙色漿液。將氯化鋁(5.421 kg,40.608 mol)緩慢添加至燒瓶中。添加前1.5 kg時放熱,得到深色溶液。添加剩餘AlCl3
,得到反應混合物。經由加料漏斗經1.5小時之時段向反應混合物中添加2,6-二氟-3-硝基苯甲醯基氯2
(2.25 kg,10.125 mol)。在添加期間,反應溫度維持在45℃或45℃以下。在添加之後,在50℃下攪拌反應混合物隔夜,冷卻至室溫(約22℃)且轉移至兩個各別20 L燒瓶中。將水(25 L)及乙腈(12 L)添加至50公升燒瓶中且冷卻至0℃。藉由添加水/乙腈溶液淬滅反應混合物,同時保持溫度在40℃或40℃以下。過濾所得混合物,且用乙腈:水(1:1,2×4 L)、水(4 L)及乙腈(4 L)洗滌濾液,繼而在真空中乾燥。獲得化合物3
。MS (ESI): M+H+
= 383.9。1
H NMR (DMSO-d6
, δ ppm): 7.55 (1 H, m), 8.47 (2 H, m), 8.53 (1 H, d, J=2.2 Hz), 8.65 (1H, d, J = 2.2Hz), 13.25 (1 H, s)。
步驟 2 . 製備 ( 3 - 胺基 - 2 , 6 - 二氟 - 苯基 )-( 5 - 溴 - 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 ) 甲酮 ( 4 )
步驟 2 . 製備 ( 3 - 胺基 - 2 , 6 - 二氟 - 苯基 )-( 5 - 溴 - 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 ) 甲酮 ( 4 )
向50公升燒瓶中添加2-甲基-四氫呋喃(2-甲基-THF) (36 L)、化合物3
(2.85 kg,7.455 mol)及氯化錫(II) (5.03 kg,22.365 mol)。將混合物加熱至60℃。完成後,用碳酸鉀水溶液(20%)淬滅反應物。用矽藻土過濾所得混合物且用2-甲基-THF及四氫呋喃(THF)洗滌固體殘餘物。用NaCl水溶液(15 L,10%)洗滌濾液且分離有機層。進一步用NaCl水溶液(15 L, 20%)洗滌有機層且在旋轉蒸發器上濃縮以得到化合物4
。MS (ESI): M+H+
= 353及354。1
H NMR (DMSO-d6
, δ ppm): 5.22 (2 H, s), 6.93 (2 H, m), 8.12 (1 H, s), 8.47 (1 H, d J=2.3 Hz), 8.54 (1 H, d J-1.6 Hz), 13.2 (1 H, s)。
步驟 3 : 製備 ( 3 - 胺基 - 2 , 6 - 二氟 - 苯基 )-[ 5 - 溴 - 1 -( 2 , 6 - 二氯苯甲醯基 ) 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 ] 甲酮 ( 5 )
步驟 3 : 製備 ( 3 - 胺基 - 2 , 6 - 二氟 - 苯基 )-[ 5 - 溴 - 1 -( 2 , 6 - 二氯苯甲醯基 ) 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 基 ] 甲酮 ( 5 )
將自步驟2獲得之化合物4
(2.5 kg, 7.114 mol)添加至50公升燒瓶中且冷卻至9.3℃。向50公升燒瓶中之化合物4
中經2小時之時段依序添加三乙胺(0.864 kg,8.537 mol)、4-二甲基胺基吡啶 (DMAP) (0.087 kg,0.7114 mol)及2,6-二氯苯甲醯基氯(1.34 kg,6.40 mol)於2-甲基-THF (25 L)中之溶液。在室溫下用甲醇(0.30 L)淬滅反應物,且添加NaCl水溶液(12.5 L,15%)及矽藻土(0.5 kg)。攪拌混合物且經由矽藻土過濾。濃縮濾液且添加5體積庚烷。攪拌所得溶液約1小時且經硫酸鈉(1 kg)乾燥且過濾。藉由在真空下移除溶劑來分離化合物5
。MS (ESI): M+H+
= 524, 525.8, 527.8。1
H NMR (DMSO-d6
, δ ppm): 5.36 (2 H, s), 7.01 (2 H, m), 7.68 (3 H, s), 8.34 (1H, brs), 8.61 (1 H, brs), 8.72 (1 H, d J=2.3 Hz)。
步驟 4 : 製備 ( 3 -( 3 - 胺基 - 2 , 6 - 二氟苯甲醯基 )- 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 1 - 基 )( 2 , 6 - 二氯苯基 ) 甲酮
步驟 4 : 製備 ( 3 -( 3 - 胺基 - 2 , 6 - 二氟苯甲醯基 )- 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 1 - 基 )( 2 , 6 - 二氯苯基 ) 甲酮
向化合物5
(40 g,0.076莫耳)及2-環丙基嘧啶-5-基-5-酉朋酸(化合物A
) (23 g,0.141 莫耳)於2-甲基四氫呋喃(2-MeTHF) (1,720 mL)中之溶液中添加8%碳酸氫鈉(經過氮氣吹掃)及雙(三苯基膦)二氯化鈀(II) (1g,0.0014莫耳)。將混合物加熱至回流以得到化合物6
,其再經過分離、洗滌及乾燥。LCMS: m/z = 564.0 (M+H)+
。1
H NMR (DMSO-d6, δ ppm): 9.05 (s, 2H), 9.00 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 7.70 (m, 3H), 7.04 (m, 2H), 5.36 (br s, 2H), 2.30 (m, 1H), 1.16 (m, 4H)。
步驟 5 : 製備 ( R )- N -( 3 -( 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1 -( 2 , 6 - 二氯苯甲醯基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 羰基 )- 2 , 4 - 二氟苯基 )- 3 - 氟吡咯啶 - 1 - 磺醯胺
步驟 5 : 製備 ( R )- N -( 3 -( 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1 -( 2 , 6 - 二氯苯甲醯基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 羰基 )- 2 , 4 - 二氟苯基 )- 3 - 氟吡咯啶 - 1 - 磺醯胺
將化合物6
(15 g,0.021莫耳)、1,4-二噁烷(150 mL)、吡啶(15 mL,49.6莫耳)及化合物B
(3-R-氟吡咯啶磺醯基氯,11.81 g,0.063莫耳)裝填至燒瓶中。在室溫下攪拌反應物,隨後加熱至50℃且使其反應隔夜。隨後將乙酸乙酯(60 mL)及水(60 mL)裝填至反應燒瓶中。分離有機層,經洗滌,使用活性炭(Darco KG-B, 2.25 g)處理,且經由矽藻土墊過濾,得到化合物7
。1
H NMR (DMSO-d6, δ ppm): 9.70 (s, 1H), 9.02 (s, 2H), 8.81 (m,2H), 8.57 (m, 2H), 7.71(m, 2H), 7.38 (m, 2H), 5.24-5.37 (2s, 1H), 3.31- 3.42 (m, 4H), 2.05 - 2.29 (m, 3H), 1.12 (m, 4H)。
藉由於二氯甲烷(293 kg)及三甲胺(32 kg)之溶液中組合市售3-R-氟吡咯啶HCl鹽(20 kg,159.3莫耳)及市售硫醯氯(21 kg,155.6莫耳)獲得化合物B
,以得到(R)-3-氟吡咯啶磺醯氯(化合物B
)。
步驟 6 : 製備 ( R )- N -( 3 -( 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 羰基 )- 2 , 4 - 二氟苯基 )- 3 - 氟吡咯啶 - 1 - 磺醯胺
步驟 6 : 製備 ( R )- N -( 3 -( 5 -( 2 - 環丙基嘧啶 - 5 - 基 )- 1H - 吡咯并 [ 2 , 3 - b ] 吡啶 - 3 - 羰基 )- 2 , 4 - 二氟苯基 )- 3 - 氟吡咯啶 - 1 - 磺醯胺
將化合物7
(26.9 kg)溶解於四氫呋喃(95.8 kg)中且將7N氨之甲醇溶液(50.2 kg)添加至反應混合物中。藉由HPLC認為反應完全後,藉由與二氯甲烷溶劑交換來分離化合物8
。將化合物8
溶解於四氫呋喃中,過濾且濃縮,且純化經分離材料,分離且於WFI (注射用水) (17.8 kg,87%產率)中濕磨。
實例 2 : 使用熱熔擠出 ( HME ) 之非晶形化合物 I 之固態分散體的製造程序
實例 2 : 使用熱熔擠出 ( HME ) 之非晶形化合物 I 之固態分散體的製造程序
化合物I之代表性配方如下文展示於表1中。
表1: 化合物I之固態分散體調配物
a
自非牛類來源獲得。
b 可基於在擠出物研磨製程期間獲得之化合物I/共聚普維酮摻合物調整量。
表1: 化合物I之固態分散體調配物
b 可基於在擠出物研磨製程期間獲得之化合物I/共聚普維酮摻合物調整量。
圖1中提供製造非晶形化合物I之固態分散體的製程流程圖。
熱熔擠出調配 ( HME ) 之 製造程序及製程控制的描述
熱熔擠出調配
熱熔擠出調配 ( HME ) 之 製造程序及製程控制的描述
熱熔擠出調配
非晶形化合物I之固態分散體可使用熱熔擠出製程來調配(在本文中被稱作調配、HME固態分散體調配或HME調配),其包含熱熔擠出、研磨、摻合,且視情況包含製錠。可組合多個熱熔擠出及研磨批次以用於摻合及製錠,從而使得分批量較大。
熱熔擠出及研磨
熱熔擠出及研磨
步驟1. 將適量化合物I (固態分散體調配物之約7.95 w/w%)及共聚普維酮(固態分散體調配物之約37.1w/w%)添加至V-摻合器。
步驟2. 摻合來自1之內容物約5分鐘且隨後篩分內容物。
步驟3. 將來自步驟2之內容物轉移回至V-摻合器且摻合約10分鐘。
步驟4. 在適合容器中對適量聚乙二醇400 (PEG400) (固態分散體調配物之約7.95 w/w%)稱重。使用額外約20 g之PEG 400來設定擠出機,且此額外約20 g之PEG 400並非調配物之部分。
步驟5. 使用適當設定點且使用來自步驟4之約20 g之PEG 400來設定擠出機以調整流動速率。
步驟6. 將來自步驟3之化合物I摻合物添加至進料斗,且開始擠出製程。根據需要調整且監測擠出參數。
步驟7. 收集所得粒化擠出物且對其稱重。
步驟8. 將粒化擠出物置放於適合容器中。
摻 合
摻 合
步驟9. 對以下材料稱重及篩選/研磨:膠態二氧化矽(固態分散體調配物之約1.0 w/w%)、交聯羧甲纖維素鈉(固態分散體調配物之約3.0 w/w%)、交聯普維酮(固態分散體調配物之約7.0 w/w%)、甘露糖醇(固態分散體調配物之約7.0 w/w%)、微晶纖維素(固態分散體調配物之約8.0 w/w%)、泊洛沙姆407 (固態分散體調配物之約6.0 w/w%)、碳酸氫鈉(固態分散體調配物之約8.0 w/w%)、氯化鈉(固態分散體調配物之約4.0 w/w%)及月桂基硫酸鈉(固態分散體調配物之約2.0 w/w%)。
步驟10.將來自步驟8之經研磨擠出物及來自步驟9之經篩選賦形劑添加至箱式摻合器且摻合約30分鐘。
步驟11. 稱出且篩選硬脂酸鎂(固態分散體調配物之約1.0 w/w%)。
步驟12. 將硬脂酸鎂添加至來自步驟10之箱式摻合器之內容物且摻合約5分鐘。
步驟13. 將來自步驟12之摻合物置放於適合、經標註容器中。
製 錠
製 錠
步驟14. 將來自步驟13之摻合物轉移至旋轉式製錠機料斗。
步驟15. 設定製錠機以產生目標錠劑重量、硬度及脆度。
步驟16. 對摻合物製錠,且約每15分鐘監測錠劑重量及硬度。
步驟17. 對來自步驟16之錠劑執行金屬檢查及重量排序。
步驟18. 可接著根據需要封裝來自步驟17之所得錠劑。
實例 3 : 使用噴霧乾燥分散 ( SDD ) 之 非晶形化合物 I 之固態分散體的製造程序
表 2 :化合物 I 之噴霧乾燥分散調配物
a
在加工期間移除。
b 大致錠劑產率:可基於最終摻合均一性之分析而調整每錠之摻合物之重量,以對最終藥品之目標100%標示值取樣。
實例 3 : 使用噴霧乾燥分散 ( SDD ) 之 非晶形化合物 I 之固態分散體的製造程序
表 2 :化合物 I 之噴霧乾燥分散調配物
b 大致錠劑產率:可基於最終摻合均一性之分析而調整每錠之摻合物之重量,以對最終藥品之目標100%標示值取樣。
圖2中提供藉由噴霧乾燥分散來製造非晶形化合物I之固態分散體的製程流程圖,及其表。
製造程序及製程控制之描述
製造程序及製程控制之描述
可使用噴霧乾燥分散方法來製造化合物I之SDD調配物,該方法包括噴霧乾燥分散以形成初始噴霧乾燥分散體;及接著進行SDD之乾式粒化及摻合以製得噴霧乾燥分散體最終摻合物。可接著在向受試者投與SDD最終摻合物之前對其製錠及封裝。
噴霧乾燥分散體 ( 初始摻合物 )- 最終摻合物之 60 % w / w
噴霧乾燥分散體 ( 初始摻合物 )- 最終摻合物之 60 % w / w
步驟1. 對噴霧溶液溶劑(丙酮及水)、HMPCAS-HG (噴霧乾燥分散體之70% w/w)、月桂基硫酸鈉(SLS) (噴霧乾燥分散體之5% w/w)及化合物I (噴霧乾燥分散體之25% w/w)稱重且放入適合容器中。
步驟2. 將SLS緩慢添加至步驟1之噴霧溶液中同時混合,接著添加化合物I,且繼續混合,直至未觀測到可見顆粒。
步驟3. 在混合期間,緩慢添加HMPCAS-HG且繼續混合,直至未觀測到固體顆粒。
步驟4. 使用標準醫藥級噴霧乾燥器(諸如,MS-150)對所得溶液進行噴霧乾燥。
步驟5. 在完成噴霧乾燥之後,在烘箱中乾燥噴霧乾燥分散體(初始摻合物)約8小時,直至殘餘丙酮低於ICH準則,5000 ppm。
步驟6. 將來自步驟5之經乾燥SDD轉移至具有除濕劑之適當容器中以免受潮。
乾式粒化及摻合
乾式粒化及摻合
步驟7. 將SDD (最終摻合物之60% w/w)及顆粒內賦形劑分配至適當容器中。所採用之顆粒內賦形劑為硬脂醯反丁烯二酸鈉(最終摻合物之0.50% w/w)、膠態二氧化矽(最終摻合物之2% w/w)、交聯羧甲纖維素鈉(最終摻合物之3% w/w)、甘露糖醇(最終摻合物之16% w/w)及微晶纖維素(最終摻合物之10.25% w/w)。
步驟8. 將SDD及顆粒內賦形劑添加至具有適當大小之摻合器且摻合12±5分鐘。
步驟9. 使摻合物通過古密爾以改良摻合均一性且移除大顆粒。
步驟10. 進一步摻合來自步驟9之摻合物且隨後排出至適當容器中。
步驟11. 對來自步驟10之摻合物進行乾式粒化以使用適當輥壓機(諸如TFC-220輥壓機或其他),使用所選擇之製程參數(輥類型、RPM及輥壓力)產生條帶。
步驟12. 使用古密爾來研磨來自步驟11之所得條帶以產生自由流動的粒化。
步驟13. 添加適量顆粒外賦形劑(硬脂醯反丁烯二酸鈉、微晶纖維素及交聯羧甲纖維素鈉)以進行粒化及摻合以獲得錠劑壓縮之摻合物。
製錠及封裝
製錠及封裝
設定旋轉式製錠機以得到目標錠劑重量、硬度及脆度。
對最終摻合物製錠,且在初始開始時且以約15分鐘間隔監測錠劑重量及硬度。
對錠劑執行金屬檢查及重量分類排序。
表3: 製程控制-噴霧乾燥分散
pXRD = 粉末X射線繞射
實例 4 : 結晶化合物 I 與 非晶形化合物 I 之固態分散體的比較性研究
表3: 製程控制-噴霧乾燥分散
實例 4 : 結晶化合物 I 與 非晶形化合物 I 之固態分散體的比較性研究
下表4提供三種調配物(亦即,結晶化合物I調配物、非晶形化合物I之固體(噴霧乾燥)分散體及化合物I之固體(熱熔擠出)分散體)之組成及其比較。
表 4 : 三種調配物之組成
USP =美國藥典公約,NF =國家處方集
a 自非牛類來源獲得。
b 甘露糖醇之量係基於化合物I之量而調整。
c 品質標準為USP-NF。
化合物 I 之結晶調配物
表 4 : 三種調配物之組成
a 自非牛類來源獲得。
b 甘露糖醇之量係基於化合物I之量而調整。
c 品質標準為USP-NF。
化合物 I 之結晶調配物
使用結晶調配物方法來開發化合物I之調配物(描述於表4中)。添加助溶劑維生素E TPGS(d-α-生育酚聚乙二醇丁二酸酯)及泊洛沙姆407以增加溶解度及生物可用性。包括額外藥典醫藥賦形劑以執行其標準作用。
結晶調配物被製造為速釋150 mg膠囊調配物且用於人體臨床研究中。在此研究中達成之最大曝露AUCτ
= 2500 ng•hr/mL (Table 2)顯著低於預期目標有效曝露(74000 ng•hr/mL)。在限制條件為存在顯著較佳的使用此結晶調配物來起始此人體臨床研究之臨床前資料的條件下,此結果為非預期的。基於此非預期後果而停止此人體臨床研究,且不再使用150 mg結晶膠囊。
表5: 化合物I之結晶調配物之藥物動力學參數
C1D1 = 循環1,第1天;C1D15 =循環1,第5天
非晶形化合物 I 之固態分散體調配物 ( 75 mg 錠劑 )
表5: 化合物I之結晶調配物之藥物動力學參數
非晶形化合物 I 之固態分散體調配物 ( 75 mg 錠劑 )
開發使用化合物I之非晶形固態分散體的調配物以克服在人體內觀測到之結晶膠囊調配物的非預期低曝露。使用熱熔擠出(HME)製程來開發固態分散體調配物。
使用本發明中描述之熱熔擠出(HME)製程來製造75 mg錠劑調配物(描述於表4中)。此75 mg錠劑用於人體臨床研究(健康志願者之單次劑量研究及癌症患者之重複劑量研究)。來自兩個研究之藥物動力學(PK)參數概述於表6及表7中。在作為75 mg HME錠劑(表6)投與之化合物I之單次劑量之後,觀測到曝露之劑量比例增加,如由Cmax
及AUC兩者表示。在重複給藥之後,在經評估之最高劑量(900 mg BID)下之穩態曝露AUCτ
= 68700 ng•hr/mL接近目標有效曝露(表7)。
表6: 人體內之化合物I之單次劑量藥物動力學參數
a
中數(最小值-最大值)。
表7: 人體內之化合物I之重複劑量藥物動力學參數
*C1D1 = 循環1,第1天;C1D15 =循環1,第15天
表6: 人體內之化合物I之單次劑量藥物動力學參數
表7: 人體內之化合物I之重複劑量藥物動力學參數
75 mg HME錠劑之一個限制為所要劑量(900 mg BID)下之高丸劑負擔。
非晶形化合物 I 之固態分散體調配物 ( 150 mg 錠劑 )
非晶形化合物 I 之固態分散體調配物 ( 150 mg 錠劑 )
使用噴霧乾燥分散技術之第二非晶形調配物開發為150 mg錠劑以減少丸劑負擔且改良了優於藉由HME製備之75 mg錠劑的錠劑物理特性。在臨床前研究中篩選數種基於SDD之錠劑調配物。基於可加工性、錠劑物理化學特性及動物體內之生物可用性而選擇非晶形化合物I之固態分散體(150 mg錠劑),如表4中所描述。在犬之單次劑量PK研究中,兩種固態分散體非晶形調配物(HME及SDD)產生類似曝露(表8)。
表8: 在兩種不同固態分散體非晶形調配物之情況下,犬體內在45 mg/kg下的化合物I之藥物動力學
表8: 在兩種不同固態分散體非晶形調配物之情況下,犬體內在45 mg/kg下的化合物I之藥物動力學
SDD錠劑調配物不僅藉由將單位劑量強度自75 mg增加至150mg來使患者丸劑負擔減少(自24減少至12個每日錠劑),且亦改良了錠劑物理特性。
實例 5 : 在存在及不存在 CYP 抑制劑下之化合物 I ( HME ) 之藥物動力學概況
實例 5 : 在存在及不存在 CYP 抑制劑下之化合物 I ( HME ) 之藥物動力學概況
CYP反應表型分析將CYP3A4鑑定為負責化合物I之代謝的主細胞色素P450酶。在階段I臨床試驗中觀測到,添加廣譜CYP抑制劑ABT或選擇性CYP3A4抑制劑考比西他阻斷化合物I之代謝。
進行階段1開放標記兩部分研究以:(i)評估化合物I之單遞升劑量的藥物動力學(PK)及安全性;及(ii)評定CYP3A4抑制劑考比西他對健康受試者體內之化合物I之PK的影響。平均年齡為37歲之總計40位成年受試者參加。A部分將受試者參加在150至900mg範圍內之化合物I之四個單次劑量組,且評估PK資料以選擇最適當的劑量水準以供用於B部分(900mg)中。在B部分中,推進來自A部分中之900 mg組的受試者完成7天清除,且隨後在第1天至第6天接收單次150 mg口服劑量之考比西他且在第3天接收單次900 mg口服劑量之化合物I;加入此組之新受試者在第13天單獨接收第二次劑量之化合物I。額外組在第1天接收單次300 mg口服劑量之化合物I,在第5天至第10天接收單次150 mg口服劑量之考比西他,且在第7天接收單次300 mg口服劑量之與考比西他共投予的化合物I。所有劑量之每種藥物係在禁食狀態下投與。此研究使用藉由熱熔擠出(HME)製程產生之化合物I之非晶形固態分散體調配物。PK參數概述於表9A及表9B中。
表9A: 化合物I之藥物動力學概況
a
呈現為中數(最小值-最大值)之Tmax
資料。
表9B: 化合物I之藥物動力學概況
表9A: 化合物I之藥物動力學概況
表9B: 化合物I之藥物動力學概況
在A部分中,化合物I在禁食狀況下作為單遞升劑量投與時展示線性PK。曝露在經研究劑量範圍150至900 mg內按比例增加劑量。B部分遵循2序列交叉設計以評估禁食狀態下考比西他(CYP3A4抑制劑)對單次口服劑量之化合物I之PK的影響。考比西他共同投與增加了化合物I曝露。相比於單獨投與之化合物I,平均值AUC0-t至AUC0 ∞增加2.6倍(300 mg水準)及3.8倍(900 mg水準),且平均值Cmax
增加1.8倍(300 mg水準)及2.7倍(900 mg水準)。
實例 6 : 在存在 CYP 抑制劑下之化合物 I ( HME ) 及 ( SDD ) 之藥物動力學概況
實例 6 : 在存在 CYP 抑制劑下之化合物 I ( HME ) 及 ( SDD ) 之藥物動力學概況
開發了使用噴霧乾燥分散技術之化合物I之非晶形固態分散體調配物以克服丸劑負擔,改良物理特性,且使得藥物能夠作為口服懸浮液來投與。
使用本發明中描述之噴霧乾燥分散(SDD)製程來製造150 mg錠劑調配物(描述於表4中)。此150 mg錠劑用於人體臨床研究(癌症患者之重複劑量研究)中。根據目標推薦階段2劑量(RP2D)曝露(AUC0 - 12
= 149,000 ng•hr/mL),化合物I [SDD] 1350 mg BID +考比西他之所得第1天AUC0 - 12
(161,000 ng•hr/mL, N=4)在標準生體相等性限制之80至125%內。化合物I [SDD] 1350 mg BID +考比西他之穩態(第15天) AUC0 - 24
(630,000 ng•hr/mL, N=3)比化合物I [HME] RP2D穩態曝露 (對於劑量遞增/N=6,AUC0 - 24
= 318,000,且對於RP2D擴展/N=22,AUC0 - 24
= 324,000 ng•hr/mL)高約1.8x。來自研究之藥物動力學(PK)參數概述於表10中。在作為150 mg SDD錠劑投與之單次劑量之化合物I(表10)之後,觀測到曝露中劑量比例自900 mg增加至2700mg,如由Cmax
及AUC兩者表示。在重複給藥之後,在經評估之最高劑量(1350 mg BID)下之穩態曝露,AUCτ
= 315,000 ng•hr/mL,接近目標有效曝露(表10)。
表 10 : 人體內之化合物 I 之重複劑量藥物動力學參數
*C1D1 =循環1,第1天;C1D15 =循環1,第15天
表 10 : 人體內之化合物 I 之重複劑量藥物動力學參數
圖1為藉由熱熔擠出來製造非晶形化合物I之固態分散體的製程流程圖。
圖2為藉由噴霧乾燥分散來製造非晶形化合物I之固態分散體的製程流程圖。
Claims (43)
- 一種固態分散體,其包含具有下式之化合物I: 化合物I, 其中化合物I為實質上非晶形。
- 如請求項1之固態分散體,其中化合物I在其固體狀態下以分子形式分散於由乙酸丁二酸羥丙基甲基纖維素(HMPCAS)形成之聚合物基質內。
- 如請求項2之固態分散體,其中該HMPCAS為HMPCAS-LF、HMPCAS-MF、HMPCAS-HF、HMPCAS-LG、HMPCAS-MG或HMPCAS-HG。
- 如請求項2至3中任一項之固態分散體,其中該HMPCAS為HMPCAS-HG。
- 如請求項2至4中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之重量比在約1:1至約1:4範圍內。
- 如請求項2至5中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之重量比在約1:2.5至約1:3.5範圍內。
- 如請求項2至6中任一項之固態分散體,其中該固態分散體內之化合物I與HMPCAS之重量比在約1:2.6至約1:2.9範圍內。
- 如請求項2至7中任一項之固態分散體,其進一步包含一或多種界面活性劑。
- 如請求項8之固態分散體,其中該一或多種界面活性劑為月桂基硫酸鈉。
- 如請求項8或9中任一項之固態分散體,其中化合物I在約15% w/w至約35% w/w範圍內;HMPCAS在約50% w/w至約85% w/w範圍內;且該一或多種界面活性劑在約1% w/w至約10% w/w範圍內。
- 如請求項8至10中任一項之固態分散體,其中化合物I在約20% w/w至約30% w/w範圍內;HMPCAS在約60% w/w至約80% w/w範圍內;且該一或多種界面活性劑在約3% w/w至約7% w/w範圍內。
- 如請求項8至11中任一項之固態分散體,其中化合物I在約22% w/w至約28% w/w範圍內;HMPCAS在約65% w/w至約75% w/w範圍內;且該一或多種界面活性劑在約4% w/w至約6% w/w範圍內。
- 如請求項8至12中任一項之固態分散體,其中化合物I為約25% w/w;HMPCAS為約70% w/w;且該一或多種界面活性劑為約5% w/w。
- 如請求項8至13中任一項之固態分散體,其進一步包含一或多種滑動劑;一或多種崩解劑;一或多種填充劑/黏合劑;及一或多種潤滑劑。
- 如請求項14之固態分散體,其中該一或多種滑動劑在約0.5% w/w至約4% w/w範圍內;該一或多種崩解劑在約3% w/w至約9% w/w範圍內;該一或多種填充劑/黏合劑在約20% w/w至約40% w/w範圍內;該一或多種潤滑劑在約0.25% w/w至約1.25% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約45.75% w/w至約76.25% w/w範圍內。
- 如請求項14之固態分散體,其中該一或多種滑動劑在約1.0% w/w至約3% w/w範圍內;該一或多種崩解劑在約4% w/w至約8% w/w範圍內;該一或多種填充劑/黏合劑在約25% w/w至約35% w/w範圍內;該一或多種潤滑劑在約0.5% w/w至約1.0% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約53% w/w至約69.5% w/w範圍內。
- 如請求項14之固態分散體,其中該一或多種滑動劑在約1.5% w/w至約2.5% w/w範圍內;該一或多種崩解劑在約5% w/w至約7% w/w範圍內;該一或多種填充劑/黏合劑在約29% w/w至約33% w/w範圍內;該一或多種潤滑劑在約0.7% w/w至約0.8% w/w範圍內;且其中化合物I、HPMCAS及界面活性劑之組合在約56.7% w/w至約63.8% w/w範圍內。
- 如請求項14至17中任一項之固態分散體,其中該一或多種滑動劑係選自由膠態二氧化矽、細微粉碎的二氧化矽、矽化微晶纖維素、氧化鎂、聚乙二醇及交聯羧甲纖維素鈉組成之群;該一或多種崩解劑係選自由碳酸氫鈉、羥基乙酸澱粉鈉、交聯羧甲纖維素鈉及交聯普維酮組成之群;該一或多種填充劑/黏合劑係選自由微晶纖維素、甘露糖醇、山梨糖醇、麥芽糊精、麥芽糖、糊精、二水合磷酸氫鈣、無水磷酸氫鈣、部分預糊化澱粉及磷酸三鈣組成之群;且該一或多種潤滑劑係選自由硬脂酸鎂、硬脂酸、棕櫚酸、硬脂酸鈣、巴西棕櫚蠟、經氫化植物油、礦物油、聚乙二醇及硬脂醯反丁烯二酸鈉組成之群。
- 如請求項14至18中任一項之固態分散體,其中該一或多種滑動劑為膠態二氧化矽;該一或多種崩解劑為交聯羧甲纖維素鈉;該一或多種填充劑/黏合劑為甘露糖醇及微晶纖維素,且該一或多種潤滑劑為硬脂醯反丁烯二酸鈉。
- 如請求項19之固態分散體,其中甘露糖醇與微晶纖維素之重量比在約2:3至約3:2範圍內。
- 如請求項19之固態分散體,其中甘露糖醇與微晶纖維素之重量比在約1.1:1.0至約1.0:1.1範圍內。
- 如請求項19至21中任一項之固態分散體,其中該微晶纖維素係選自由Avicel PH-101、Avicel PH-102、Avicel PH-105、Avicel PH-112及其組合組成之群。
- 如請求項19至22中任一項之固態分散體,其中該微晶纖維素為Avicel PH-105與Avicel PH-101之組合。
- 如請求項19至23中任一項之固態分散體,其中顆粒內微晶纖維素為Avicel PH-105,且顆粒外微晶纖維素為Avicel PH-101。
- 如請求項24之固態分散體,其中Avicel PH-105與Avicel PH-101之比率為約1:1至約1:3。
- 如請求項25之固態分散體,其中Avicel PH-105與Avicel PH-101之比率為約1:1.8至約1:2.2。
- 如請求項1之固態分散體,其進一步包含一或多種助溶劑。
- 如請求項27之固態分散體,其中該一或多種助溶劑係選自由以下各者組成之群:牛膽酸鈉、拉巴索(Labrasol)、泊洛沙姆(poloxamer)、聚乙二醇、共聚普維酮(copovidone)、Transcutol P、丙二醇、Gelucire 44/14、HCO-60、乙醇、Cremophor EL、Tween 80、2-羥丙基-β-環糊精及二甲亞碸。
- 如請求項28之固態分散體,其中該一或多種助溶劑係選自由泊洛沙姆407、聚乙二醇400及共聚普維酮組成之群。
- 如請求項27至29中任一項之固態分散體,其進一步包含一或多種滑動劑;一或多種崩解劑;一或多種填充劑/黏合劑;一或多種潤滑劑;一或多種界面活性劑;及一或多種滲透原。
- 如請求項30之固態分散體,其中化合物I在約5% w/w至約12% w/w範圍內;該一或多種助溶劑在約35% w/w至約65% w/w範圍內;該一或多種滑動劑在約0.5% w/w至約2% w/w範圍內;該一或多種填充劑/黏合劑在約8% w/w至約22% w/w範圍內;該一或多種界面活性劑在約0.5% w/w至約4% w/w範圍內;該一或多種崩解劑在約12% w/w至約24% w/w範圍內;該一或多種潤滑劑在約0.25% w/w至約3.0% w/w範圍內;且該一或多種滲透原在約2% w/w至約6% w/w範圍內。
- 如請求項30之固態分散體,其中化合物I在約7% w/w至約10% w/w範圍內;該一或多種助溶劑在約45% w/w至約55% w/w範圍內;該一或多種滑動劑在約0.75% w/w至約1.5% w/w範圍內;該一或多種填充劑/黏合劑在約12% w/w至約18% w/w範圍內;該一或多種界面活性劑在約1.0% w/w至約3% w/w範圍內;該一或多種崩解劑在約16% w/w至約20% w/w範圍內;該一或多種潤滑劑在約0.50% w/w至約2% w/w範圍內;且該一或多種滲透原在約3% w/w至約5% w/w範圍內。
- 如請求項30之固態分散體,其中化合物I在約7.5% w/w至約8.5% w/w範圍內;該一或多種助溶劑在約48% w/w至約52% w/w範圍內;該一或多種滑動劑在約0.9% w/w至約1.1% w/w範圍內;該一或多種填充劑/黏合劑在約14% w/w至約16% w/w範圍內;該一或多種界面活性劑在約1.5% w/w至約2.5% w/w範圍內;該一或多種崩解劑在約17% w/w至約19% w/w範圍內;該一或多種潤滑劑在約0.75% w/w至約1.25% w/w範圍內;且該一或多種滲透原在約3.5% w/w至約4.55% w/w範圍內。
- 如請求項30至33中任一項之固態分散體,其中該一或多種界面活性劑係選自由泊洛沙姆407、聚乙二醇400及共聚普維酮組成之群;該一或多種滑動劑係選自由膠態二氧化矽、細微粉碎的二氧化矽、矽化微晶纖維素、氧化鎂、聚乙二醇及交聯羧甲纖維素鈉組成之群;該一或多種崩解劑係選自由碳酸氫鈉、羥基乙酸澱粉鈉、交聯羧甲纖維素鈉及交聯普維酮組成之群;該一或多種填充劑/黏合劑係選自由微晶纖維素、甘露糖醇、山梨糖醇、麥芽糊精、麥芽糖、糊精、二水合磷酸氫鈣、無水磷酸氫鈣、部分預糊化澱粉及磷酸三鈣組成之群;該一或多種潤滑劑係選自由硬脂酸鎂、硬脂酸、棕櫚酸、硬脂酸鈣、巴西棕櫚蠟、經氫化植物油、礦物油、聚乙二醇及硬脂醯反丁烯二酸鈉組成之群;該界面活性劑為月桂基硫酸鈉;且該滲透原為氯化鈉。
- 如請求項34之固態分散體,其中該一或多種界面活性劑為泊洛沙姆407、聚乙二醇400及共聚普維酮;該一或多種滑動劑為膠態二氧化矽;該一或多種崩解劑為碳酸氫鈉、交聯羧甲纖維素鈉及交聯普維酮;該一或多種填充劑/黏合劑為微晶纖維素及甘露糖醇;該潤滑劑為硬脂酸鎂;該界面活性劑為月桂基硫酸鈉;且該滲透原為氯化鈉。
- 如請求項1至35中任一項之固態分散體,其中該組合物呈適用於口服劑量之錠劑形式。
- 如請求項36之固態分散體,其中該錠劑懸浮於水或含水溶劑中。
- 一種如請求項1至36中任一項之固態分散體的用途,其用於製造用以治療BRAF突變相關之疾病或病狀之藥物,其中該BRAF突變相關之疾病或病狀為黑色素瘤、結腸直腸癌、乳頭狀甲狀腺癌、乳頭狀顱咽管瘤、多形性甲狀腺癌、卵巢癌、非小細胞肺癌、胃癌、膽管癌、巴雷特氏食道癌(Barrett's esophageal cancer)、頭頸癌、肝細胞癌、乳癌、蘭格漢氏(Langerhan’s)細胞組織細胞增多病、胃腸道基質細胞腫瘤(GIST)、多發性骨髓瘤、小兒星形細胞瘤、多形性黃星形細胞瘤、慢性骨髓性白血病、急性骨髓單核細胞性白血病、雙表型B骨髓單核細胞性白血病、急性骨髓性白血病、毛細胞白血病、痣、埃德海姆-切斯特病(Erdheim-Chester Disease)、惡性周邊神經鞘腫瘤、發炎及自體免疫疾病、腱鞘巨細胞瘤、色素沉著絨毛結節性滑膜炎、肌腱鞘巨細胞瘤、骨巨細胞瘤、子宮頸癌、子宮內膜癌、生殖細胞腫瘤、前列腺癌、膀胱癌、肌周細胞瘤、後腎腺瘤、胰腺贅瘤、神經內分泌腫瘤、內分泌腫瘤、腎上腺腫瘤、腎上腺髓質腫瘤、腮腺囊腺癌、多形性膠質母細胞瘤、包括膽管腺瘤之膽管癌(bile duct cancer)、膽管癌(choloangiocarcinoma)、B細胞慢性淋巴增生病症、樹突狀細胞肉瘤、組織細胞肉瘤、或淋巴瘤。
- 如請求項38之用途,其中該BRAF突變相關之疾病或病狀為肝細胞癌、蘭格漢氏細胞組織細胞增多病、埃德海姆-切斯特病、胃腸道基質細胞腫瘤、毛細胞白血病、黑色素瘤、結腸直腸癌、乳頭狀甲狀腺癌、多形性甲狀腺癌、卵巢癌、非小細胞肺癌、結腸直腸癌、多形性膠質母細胞瘤、前列腺癌、胃癌、膽管癌或巴雷特氏食道癌。
- 如請求項38至39中任一項之用途,其中該藥物係與CYP抑制劑共同投與。
- 如請求項40之用途,其中該CYP抑制劑為CYP3A抑制劑。
- 如請求項41之用途,其中該CYP3A抑制劑為波普瑞韋(boceprevir)、考比西他(cobicistat)、考尼伐坦(conivaptan)、丹諾普韋(danoprevir)及利托那韋(ritonavir)、埃替格韋(elvitegravir)及利托那韋(ritonavir)、葡萄柚汁、茚地那韋及利托那韋(ritonavir)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、洛匹那韋(lopinavir)及利托那韋(ritonavir)、泊沙康唑(posaconazole)、利托那韋(ritonavir)、沙奎那韋(saquinavir)及利托那韋(ritonavir)、特拉匹韋(telaprevir)、替拉那韋(tipranavir)及利托那韋(ritonavir)、醋竹桃黴素(troleandomycin)、伏立康唑(voriconazole)、克拉黴素(clarithromycin)、地爾硫卓(diltiazem)、艾德斯布(idelalisib)、奈法唑酮(nefazodone)、奈非那韋(nelfinavir)或帕瑞普韋和(paritaprevir)及利托那韋(ritonavir)及奧比他韋(ombitasvir)及/或達薩布韋(dasabuvir)。
- 如請求項42之用途,其中該CYP3A抑制劑為考比西他。
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Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2170830B1 (en) | 2007-07-17 | 2014-10-15 | Plexxikon, Inc. | 2-FLUORO-BENZENESULFONAMIDE COMPOUNDS AS Raf KINASE MODULATORS |
TR201816421T4 (tr) | 2011-02-07 | 2018-11-21 | Plexxikon Inc | Kinaz modülasyonu için bileşikler ve metotlar ve bunların endikasyonları. |
KR102244719B1 (ko) | 2013-03-15 | 2021-04-26 | 플렉시콘 인코퍼레이티드 | 헤테로시클릭 화합물 및 그의 용도 |
US20140303121A1 (en) | 2013-03-15 | 2014-10-09 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
HUE047657T2 (hu) | 2015-05-06 | 2020-05-28 | Plexxikon Inc | Kináz-moduláló hatású 1H-pirrolo[2,3-b]piridin származékok szintézise |
KR20180052757A (ko) | 2015-09-21 | 2018-05-18 | 플렉시콘 인코퍼레이티드 | 헤테로시클릭 화합물 및 그의 용도 |
WO2019075243A1 (en) | 2017-10-13 | 2019-04-18 | Plexxikon Inc. | SOLID FORMS OF A COMPOUND FOR MODULATING KINASES |
CN112119072A (zh) | 2018-03-20 | 2020-12-22 | 普莱希科公司 | 用于ido和tdo调节的化合物和方法,以及其适应症 |
EP3953351A1 (en) | 2019-04-09 | 2022-02-16 | Plexxikon Inc. | Condensed azines for ep300 or cbp modulation and indications therefor |
WO2020236083A1 (en) * | 2019-05-22 | 2020-11-26 | Agency For Science, Technology And Research | Oral formulations, methods of manufacture and uses thereof |
MX2022001863A (es) | 2019-08-12 | 2022-05-30 | Deciphera Pharmaceuticals Llc | Metodos para tratar los tumores del estroma gastrointestinal. |
RS65058B1 (sr) | 2019-12-30 | 2024-02-29 | Deciphera Pharmaceuticals Llc | Formulacije inhibitora amorfne kinaze i postupci njihove primene |
BR112022013169A2 (pt) | 2019-12-30 | 2022-09-13 | Deciphera Pharmaceuticals Llc | Composições de 1-(4-bromo-5-(1-etil-7-(metilamino)-2-oxo-1,2-diidro-1,6-naftiridin-3-il)-2-fluorofeil)-3-fenilurea |
EP4139296A1 (en) | 2020-04-23 | 2023-03-01 | Opna Immuno Oncology, SA | Compounds and methods for cd73 modulation and indications therefor |
WO2022040512A1 (en) | 2020-08-21 | 2022-02-24 | Plexxikon Inc. | Combinational drug anticancer therapies |
CN112022850A (zh) * | 2020-09-30 | 2020-12-04 | 郑州大学 | 埃替拉韦在制备抗肿瘤药物中的应用 |
CN112168826B (zh) * | 2020-09-30 | 2021-09-21 | 郑州大学 | 达塞布韦在制备抗食管癌和胃癌肿瘤药物中的应用 |
CN116444525A (zh) * | 2023-03-27 | 2023-07-18 | 成都苑东生物制药股份有限公司 | 一种盐酸泊那替尼a晶型的制备方法 |
Family Cites Families (79)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040171062A1 (en) | 2002-02-28 | 2004-09-02 | Plexxikon, Inc. | Methods for the design of molecular scaffolds and ligands |
CA2503905A1 (en) | 2002-09-16 | 2004-03-25 | Plexxikon, Inc. | Crystal structure of pim-1 kinase |
US20050048573A1 (en) | 2003-02-03 | 2005-03-03 | Plexxikon, Inc. | PDE5A crystal structure and uses |
WO2004078923A2 (en) | 2003-02-28 | 2004-09-16 | Plexxikon, Inc. | Pyk2 crystal structure and uses |
US20050079548A1 (en) | 2003-07-07 | 2005-04-14 | Plexxikon, Inc. | Ligand development using PDE4B crystal structures |
US7348338B2 (en) | 2003-07-17 | 2008-03-25 | Plexxikon, Inc. | PPAR active compounds |
JP4845730B2 (ja) | 2003-07-17 | 2011-12-28 | プレキシコン,インコーポレーテッド | Ppar活性化合物 |
US20050164300A1 (en) | 2003-09-15 | 2005-07-28 | Plexxikon, Inc. | Molecular scaffolds for kinase ligand development |
US7517970B2 (en) | 2003-12-19 | 2009-04-14 | Plexxikon, Inc. | Nucleic acids encoding kinase and phosphatase enzymes, expression vectors and cells containing same |
CA2550361C (en) | 2003-12-19 | 2014-04-29 | Prabha Ibrahim | Compounds and methods for development of ret modulators |
US20070066641A1 (en) | 2003-12-19 | 2007-03-22 | Prabha Ibrahim | Compounds and methods for development of RET modulators |
JP2008503446A (ja) | 2004-05-06 | 2008-02-07 | プレキシコン,インコーポレーテッド | Pde4b阻害剤及びその使用 |
US7498342B2 (en) | 2004-06-17 | 2009-03-03 | Plexxikon, Inc. | Compounds modulating c-kit activity |
AU2005265017A1 (en) | 2004-06-17 | 2006-01-26 | Plexxikon, Inc. | Azaindoles modulating c-kit activity and uses therefor |
US7605168B2 (en) | 2004-09-03 | 2009-10-20 | Plexxikon, Inc. | PDE4B inhibitors |
EP1833787A2 (en) | 2004-11-30 | 2007-09-19 | Plexxikon, Inc. | Indole derivatives for use as ppar active compounds |
WO2006060456A2 (en) | 2004-11-30 | 2006-06-08 | Plexxikon, Inc. | Indole derivatives for use as ppar ppar active compounds |
US20060160135A1 (en) | 2004-12-08 | 2006-07-20 | Weiru Wang | SF-1 and LRH-1 modulator development |
MX2007014377A (es) | 2005-05-17 | 2008-02-06 | Plexxikon Inc | Inhibidores de proteina cinasa de derivados de pirrol (2,3-b) piridina. |
BRPI0611863B1 (pt) | 2005-06-22 | 2021-11-23 | Plexxikon, Inc | Composto, bem como composição e kit compreendendo o mesmo, composto intermediário na preparação do mesmo, método para tratamento e uso do mesmo |
KR20080047591A (ko) | 2005-09-07 | 2008-05-29 | 플렉시콘, 인코퍼레이티드 | Ppar 조절인자로서 사용하기 위한 1,3-이치환된 인돌유도체 |
US20080234349A1 (en) | 2005-09-07 | 2008-09-25 | Jack Lin | PPAR active compounds |
AU2006287521A1 (en) | 2005-09-07 | 2007-03-15 | Plexxikon, Inc. | PPARactive compounds |
KR100767349B1 (ko) * | 2006-08-01 | 2007-10-17 | 삼천당제약주식회사 | 페노피브레이트를 함유하는 경구용 약제 조성물 및 그의제조방법 |
WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
RU2009122670A (ru) | 2006-12-21 | 2011-01-27 | Плекссикон, Инк. (Us) | Соединения и способы для модуляции киназ и показания к их применению |
PE20121126A1 (es) | 2006-12-21 | 2012-08-24 | Plexxikon Inc | Compuestos pirrolo [2,3-b] piridinas como moduladores de quinasa |
WO2008079909A1 (en) | 2006-12-21 | 2008-07-03 | Plexxikon, Inc. | Pyrrolo [2,3-b] pyridines as kinase modulators |
AU2008222807A1 (en) | 2007-03-08 | 2008-09-12 | Plexxikon, Inc. | PPAR active compounds |
PE20090159A1 (es) | 2007-03-08 | 2009-02-21 | Plexxikon Inc | COMPUESTOS DERIVADOS DE ACIDO INDOL-PROPIONICO COMO MODULADORES PPARs |
EP2170830B1 (en) | 2007-07-17 | 2014-10-15 | Plexxikon, Inc. | 2-FLUORO-BENZENESULFONAMIDE COMPOUNDS AS Raf KINASE MODULATORS |
PE20091846A1 (es) | 2008-05-19 | 2009-12-16 | Plexxikon Inc | DERIVADOS DE PIRROLO[2,3-d]-PIRIMIDINA COMO MODULADORES DE CINASAS |
US8158636B2 (en) | 2008-05-19 | 2012-04-17 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
AU2009257635A1 (en) | 2008-06-10 | 2009-12-17 | Plexxikon, Inc. | 5H-Pyrrolo [2,3-b] pyrazine derivatives for kinase modulation, and indications therefor |
WO2009152087A1 (en) | 2008-06-10 | 2009-12-17 | Plexxikon, Inc. | Bicyclic heteroaryl compounds and methods for kinase modulation, and indications therefor |
CN102421775A (zh) | 2009-03-11 | 2012-04-18 | 普莱希科公司 | 抑制Raf激酶的吡咯并[2,3-b]吡啶衍生物 |
CN102421776A (zh) | 2009-03-11 | 2012-04-18 | 普莱希科公司 | 抑制Raf激酶的吡咯并[2,3-b]吡啶衍生物 |
WO2010111527A1 (en) | 2009-03-26 | 2010-09-30 | Plexxikon, Inc. | Pyrazolo [ 3, 4 -b] pyridines as kinase inhibitors and their medical use |
MY172424A (en) | 2009-04-03 | 2019-11-25 | Hoffmann La Roche | Propane- i-sulfonic acid {3- (4-chloro-phenyl)-1h-pyrrolo [2, 3-b] pyridine-3-carconyl] -2, 4-difluoro-phenyl} -amide compositions and uses thereof |
MX2011011735A (es) | 2009-05-04 | 2011-11-29 | Plexxikon Inc | Compuestos y metodos para la inhibicion de renina, e indicaciones para ello. |
TW201041888A (en) | 2009-05-06 | 2010-12-01 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
WO2010143199A1 (en) * | 2009-06-11 | 2010-12-16 | Suven Nishtaa Pharma Private Limited | Solid lipid dispersion for aqueous solubility enhancement of poorly water soluble drugs |
BR112012012156A2 (pt) | 2009-11-06 | 2015-09-08 | Plexxikon Inc | compostos e métodos para modulação de cinase, e indicações para esta |
ES2627911T3 (es) | 2009-11-18 | 2017-08-01 | Plexxikon, Inc. | Derivados de N-[2-fluoro-3-(4-amino-7H-pirrolo[2,3-d]pirimidin-5-carbonil)-fenil]-4-bencenosulfonamida como moduladores de la proteína quinasa Raf para el tratamiento del cáncer |
AU2010336524B2 (en) | 2009-12-23 | 2015-10-08 | Plexxikon, Inc. | Compounds and methods for kinase modulation, and indications therefor |
TWI619713B (zh) | 2010-04-21 | 2018-04-01 | 普雷辛肯公司 | 用於激酶調節的化合物和方法及其適應症 |
MX2012014849A (es) * | 2010-06-14 | 2013-05-01 | Dow Global Technologies Llc | Acetato succinato de hidroxipropil metil celulosa con substitucion de acetato de y succinato intensificada. |
US8642606B2 (en) | 2010-09-29 | 2014-02-04 | Plexxikon Inc. | ZAP-70 active compounds |
TR201816421T4 (tr) * | 2011-02-07 | 2018-11-21 | Plexxikon Inc | Kinaz modülasyonu için bileşikler ve metotlar ve bunların endikasyonları. |
AR085279A1 (es) | 2011-02-21 | 2013-09-18 | Plexxikon Inc | Formas solidas de {3-[5-(4-cloro-fenil)-1h-pirrolo[2,3-b]piridina-3-carbonil]-2,4-difluor-fenil}-amida del acido propano-1-sulfonico |
AU2012255275B2 (en) | 2011-05-17 | 2016-01-28 | Plexxikon Inc. | Kinase modulation and indications therefor |
US20150011525A1 (en) * | 2011-09-13 | 2015-01-08 | Isp Investments Inc. | Solid dispersion of poorly soluble compounds comprising crospovidone and at least one water-soluble polymer |
US9358235B2 (en) | 2012-03-19 | 2016-06-07 | Plexxikon Inc. | Kinase modulation, and indications therefor |
US9150570B2 (en) | 2012-05-31 | 2015-10-06 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
US10227357B2 (en) | 2012-09-06 | 2019-03-12 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
KR102212923B1 (ko) | 2012-12-21 | 2021-02-04 | 플렉시콘 인코퍼레이티드 | 키나제 조절을 위한 화합물 및 방법, 및 그에 대한 적응증 |
KR102244719B1 (ko) | 2013-03-15 | 2021-04-26 | 플렉시콘 인코퍼레이티드 | 헤테로시클릭 화합물 및 그의 용도 |
US20140303121A1 (en) | 2013-03-15 | 2014-10-09 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
SG11201509338QA (en) | 2013-05-30 | 2015-12-30 | Plexxikon Inc | Compounds for kinase modulation, and indications therefor |
US9771369B2 (en) | 2014-03-04 | 2017-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
EP3194392B1 (en) | 2014-09-15 | 2020-01-01 | Plexxikon, Inc. | Heterocyclic compounds and uses thereof |
EP3237412A4 (en) * | 2014-12-22 | 2018-10-17 | Merck Sharp & Dohme Corp. | Solid dispersion formulations of antiviral compounds |
US10160755B2 (en) | 2015-04-08 | 2018-12-25 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9802932B2 (en) | 2015-05-06 | 2017-10-31 | Plexxikon Inc. | Solid forms of a compound modulating kinases |
HUE047657T2 (hu) | 2015-05-06 | 2020-05-28 | Plexxikon Inc | Kináz-moduláló hatású 1H-pirrolo[2,3-b]piridin származékok szintézise |
CN107771178B (zh) | 2015-05-22 | 2021-04-06 | 普莱希科公司 | 杂环化合物的合成 |
US9814714B2 (en) | 2015-05-22 | 2017-11-14 | Plexxikon Inc. | Kinase modulation, and indications therefor |
KR102369405B1 (ko) * | 2015-06-04 | 2022-03-02 | 화이자 인코포레이티드 | 팔보시클립의 고체 투여 형태 |
WO2017019804A2 (en) | 2015-07-28 | 2017-02-02 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US20180228826A1 (en) * | 2015-08-04 | 2018-08-16 | Merck Sharp & Dohme Corp. | Fixed-dose combinations of antiviral compounds |
KR20180052757A (ko) | 2015-09-21 | 2018-05-18 | 플렉시콘 인코퍼레이티드 | 헤테로시클릭 화합물 및 그의 용도 |
US9938273B2 (en) | 2015-12-07 | 2018-04-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
EP3430005B1 (en) | 2016-03-16 | 2021-12-08 | Plexxikon Inc. | Compounds and methods for kinase modulation and indications therefore |
TW201815766A (zh) | 2016-09-22 | 2018-05-01 | 美商普雷辛肯公司 | 用於ido及tdo調節之化合物及方法以及其適應症 |
CA3047580A1 (en) | 2016-12-23 | 2018-07-26 | Plexxikon Inc. | Compounds and methods for cdk8 modulation and indications therefor |
US10577366B2 (en) | 2017-03-20 | 2020-03-03 | Plexxikon Inc. | Crystalline forms of a compound that inhibits bromodomain |
US10428067B2 (en) | 2017-06-07 | 2019-10-01 | Plexxikon Inc. | Compounds and methods for kinase modulation |
US10435404B2 (en) | 2017-07-25 | 2019-10-08 | Plexxikon Inc. | Formulations of a compound modulating kinases |
WO2019075243A1 (en) | 2017-10-13 | 2019-04-18 | Plexxikon Inc. | SOLID FORMS OF A COMPOUND FOR MODULATING KINASES |
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US20190125747A1 (en) | 2019-05-02 |
IL273947A (en) | 2020-05-31 |
CA3080197C (en) | 2023-12-19 |
US20220184079A1 (en) | 2022-06-16 |
TWI803530B (zh) | 2023-06-01 |
BR112020007972A2 (pt) | 2020-10-20 |
CN112165958A (zh) | 2021-01-01 |
AU2018354423A1 (en) | 2020-05-14 |
WO2019084462A1 (en) | 2019-05-02 |
JP2021501142A (ja) | 2021-01-14 |
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