TW201113050A

TW201113050A - 3-cyanoquinoline tablet formulations and uses thereof

Info

Publication number: TW201113050A
Application number: TW099121740A
Authority: TW
Inventors: Ramarao Chatlapalli; Krishnendu Ghosh; Goldi Kaul; Arwinder Nagi
Original assignee: Wyeth Llc
Priority date: 2009-07-02
Filing date: 2010-07-01
Publication date: 2011-04-16
Also published as: ZA201200366B; JP2011012063A; RU2011152105A; BRPI1015941A2; CN102470109A; MX2012000048A; SG177309A1; IL217298A0; KR20120046216A; WO2011002857A3; EP2448563A2; CA2766067A1; WO2011002857A2; AU2010266342A1; AR077546A1

Abstract

The present invention provides solid compositions comprising a 3-cyanoquinoline, SKI-606, and further comprising croscarmellose sodium, Tween, or both.

Description

201113050 六、發明說明：【發明所屬之技術領域】本發明係關於某些氰基喹啉化合物之調配物。特定而言，本發明係關於一種穩定錠劑，其包括3氰基喹啉化合 .物，即4-(2,4-二氯-5-甲氧基_苯基胺基）_6_甲氧基_7[3_(4σ_ 甲基-六氫吡嗪·1_基）·丙氧基]-喹啉-3_甲腈，且進一步包括超崩解劑交聯羧甲纖維素鈉、表面活性劑聚氧乙烯山梨醇酐單油酸酯（聚山梨醇酯/聚氧乙烯山梨醇酐單油酸酯 (Tween-80TM))、或二者。【先前技術】某些3-氰基喹啉化合物及其醫藥上可接受之鹽係蛋白激酶抑制劑且具有抗腫瘤活性，且因此用於治療至少部分地源自此受體失調之某些疾病狀態（例如癌症）。受體酪胺酸激酶對於引發細胞複製之生物化學信號之傳輸甚為重要。其係跨細胞膜之較大的酶且具有用於生長因子（例如表皮生長因子受體（EGFR))之細胞外結合結構域及細胞内部分 (其用作激酶以使蛋白質中之酪胺酸胺基酸磷酸化），且因此可影響細胞增殖。基於可結合不同受體酪胺酸激酶之生長因子家族，業内已知各種類型受體酪胺酸激酶（Wilks， Advances in Cancer Researeh，1993, 6〇, 43 73)。該分類法 •包含Ϊ類受體酪胺酸激酶（包括EGFR家族之受體酪胺酸激酶’例如EGFR、TGFa ' Neu及erbB受體）、II類受體酪胺酸激酶（包括胰島素家族之受體酪胺酸激酶，例如胰島素及IGFI受體及胰島素相關性受體（以尺乃及⑴類受體酪胺酸 149415.doc 201113050 激酶（包括血小板衍生性生長因子（PDGF)家族之受體酪胺酸激酶，例如PDGFci、PDGFP及菌落刺激因子1 (CSF1)受體）。亦·眾所周知，某些酪胺酸激酶屬於非受體酪胺酸激酶類’其位於細胞内且參與生物化學信號（例如彼等影響腫瘤細胞之運動、擴散及侵入及隨後轉移性腫瘤生長者）之傳輸（Ulkich等人，Cell，1990，61, 203-212、Bolen等人， FASEB J·，1992，6，3403-3409、Brickell 等人，Critical Reviews in Oncogenesis，1992，3，401-406、Bohlen等人， Oncogene, 1993，8 2025-2031、Courtneidge 等人，Semin. Cancer Biol., 1994, 5，239-246、Lauffenburger等人，Cell, 1996，84，359-369、Hanks等人，BioEssays，1996，19，137-145、Parsons等人，Current Opinion in Cell Biology, 1997, 9，187-192、Brown等人，Biochimica et Biophysica Acta, 1996， 1287， 121-149 及 Schlaepfer 等人，Progress in201113050 VI. Description of the Invention: [Technical Field to Which the Invention Is Ascribed] The present invention relates to a formulation of certain cyanoquinoline compounds. In particular, the present invention relates to a stable tablet comprising a 3-cyanoquinoline compound, namely 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy Base_7[3_(4σ_methyl-hexahydropyrazine·1_yl)·propoxy]-quinoline-3-carbonitrile, and further includes super disintegrant croscarmellose sodium, surface active A polyoxyethylene sorbitan monooleate (polysorbate/polyoxyethylene sorbitan monooleate (Tween-80TM)), or both. [Prior Art] Certain 3-cyanoquinoline compounds and their pharmaceutically acceptable salt-based protein kinase inhibitors have antitumor activity and are therefore useful in the treatment of certain diseases at least partially derived from this receptor disorder Status (eg cancer). Receptor tyrosine kinases are important for the transmission of biochemical signals that trigger cell replication. It is a larger enzyme across the cell membrane and has an extracellular binding domain and an intracellular portion for growth factors such as the epidermal growth factor receptor (EGFR), which acts as a kinase to make the tyrosine amine in the protein. Phosphorylation of the base acid, and thus can affect cell proliferation. Various types of receptor tyrosine kinases are known in the art based on a family of growth factors that bind to different receptor tyrosine kinases (Wilks, Advances in Cancer Researeh, 1993, 6〇, 43 73). This classification includes steroid receptor tyrosine kinases (including the EGFR family of receptor tyrosine kinases such as EGFR, TGFa 'Ne and erbB receptors), and class II receptor tyrosine kinases (including the insulin family) Receptor tyrosine kinases, such as insulin and IGFI receptors and insulin-related receptors (receptor of the tyrosine and tyrosine tyrosine 149415.doc 201113050 kinase (including the receptor for the platelet-derived growth factor (PDGF) family) Tyrosine kinases, such as PDGFci, PDGFP, and colony stimulating factor 1 (CSF1) receptors. Also known, certain tyrosine kinases are non-receptor tyrosine kinases that are located intracellularly and are involved in biochemical signals. (eg, those that affect the movement, spread, and invasion of tumor cells and subsequent metastatic tumor growth) (Ulkich et al, Cell, 1990, 61, 203-212, Bolen et al, FASEB J., 1992, 6, 3403-3409, Brickell et al, Critical Reviews in Oncogenesis, 1992, 3, 401-406, Bohlen et al, Oncogene, 1993, 8 2025-2031, Courtneidge et al, Semin. Cancer Biol., 1994, 5, 239- 246, Lauffenburger Et al, Cell, 1996, 84, 359-369, Hanks et al, BioEssays, 1996, 19, 137-145, Parsons et al, Current Opinion in Cell Biology, 1997, 9, 187-192, Brown et al, Biochimica Et Biophysica Acta, 1996, 1287, 121-149 and Schlaepfer et al., Progress in

Biophysics and Molecular Biology, 1999，71，435-478)。業内已知各種類型之非受體酪胺酸激酶，其包含Src家族（例如Src、Lyn及Yes酪胺酸激酶）、Abl家族（例如Abl及Arg)及 Jak家族（例如Jak 1及Tyk 2)。 3-氰基喹啉化合物4-(2,4-二氯-5-曱氧基-苯基胺基）-6-甲氧基- 7- [3-(4-甲基-六氫。比。秦-1-基）-丙氧基]-啥琳_3_甲腈亦稱作SKI-606或伯舒替尼（bosutinib)，其係在pH 8.0下固有溶解度為約0.06 pg/mL之弱鹼。在pH小於8時，化合物 SKI-606之溶解度由於電離而隨PH降低指數性增加。然 149415.doc 201113050 而，在低pH水溶液（PH為3及更低）中觀察到3幻_6〇6經由水解毛生为解，但該化合物在p Η面於5時相對穩定。關於現有3·氰基喧琳固體調配物之一些問題包含易變的溶解作用，此似乎取決於活性醫藥成份（Αρι)之粒徑。與典型情形相反，在與用於較大API(D9〇約為4〇微米）之相似處理條件下，pin調配物中之較小API(D9〇約為2〇微米）似乎阻礙溶解作用，從而導致不能達到溶解規範。使用較大錠劑（較高強度）時尤其能觀察到此情形。此外，亦觀察到調配物在陳化/儲存後之較早時間點處具有加速溶解特性（在室溫及加速條件下，陳化後之溶解作用具有較小但顯著的移位）。結果呈現於以下兩種溶解方法中：0.1 N HC1法及CTAB/pH 5乙酸鹽法，且進一步論述於下文中。選擇後一方法來更好地展示在長達3〇分鐘之時間點中之溶解曲線’此乃因發現〇.1 N HC1法在最初之 10-20分鐘内即已釋放所有藥物。因此，期望提供用於患者之3 -氰基啥琳化合物（例如‘ (2，4_二氣-5-曱氧基-苯基胺基）_6_曱氧基-7-[3-(4-曱基-六氫°比嗪-1-基）-丙氧基]-喹啉-3-曱腈）的穩定固體調配物，其不受API粒徑變化影響且在陳化及儲存期間比較穩定。【發明内容】本發明揭示兩種創新技術：改變崩解劑類型（及崩解劑比率）以改善溶解及穩定性；及使用諸如聚氧乙烯山梨醇肝單油酸酯（聚山梨醇酯/聚氧乙烯山梨醇酐單油酸酯 (Tween-80))等液體表面活性劑代替泊洛沙姆（p〇i〇xamer)以 149415.doc 201113050 亦改善溶解及穩定性。在第一實施例中，本發明提供3·氰基喹啉之醫藥上可接受之固體組合物，其包括4-(2,4_二氣甲氧基:苯基胺基）-6-甲氧基-7·[3-(4-甲基-六氫》比嗅·！ ·基）·丙氧基卜啥淋-3-曱腈。在某些實施财’提供鍵劑形式之該等固體二合物。在一些實施例中，本發明提供包括4_(2,4_二氯·^甲氧基-苯基胺基）-6-甲氧基-7-[3·(4_曱基_六氫β比嘻_丨基）丙氧基]-喹琳-3-甲腈之單位劑型。本發明提供包括以下物質作為粒内組份之醫藥上可接受 =且合物：以組合物重量計，⑷180重量％、或3〇·8(^ 量％之4-(2,4-二氯·5_甲氧基-苯基胺基）·6曱氧基-7[3_(4_ 曱基-六氫°比嗪-1-基）·丙氧基]•喹啉-3-甲腈；及（b) cm-20 重量％之一或多種潤濕劑。本發明提供包括以下物質作為粒内組份之醫藥上可接受之組合物：以組合物重量計，⑷25-80重量％、或30_80重里％之4-(2,4-二氯·5·甲氧基·苯基胺基）_6_甲氧基_7_[3_(4_ 曱基氫吼嗪基）·丙氧基]-喹啉-3-曱腈；及（b) 0.1-20 重畺/〇之或多種潤濕劑，其中組合物之粒内組份進一步佔4 ’’且&物之82·5重量％且粒外組份佔該組合物之丨7 5重量〇/〇。本發明提供包括以下之醫藥上可接受之組合物：粒内組伤（勾25-80重量〇/〇、或30-80重量〇/0之4-(2,4-二氣-5-甲氧基_ 苯基胺基）·6-甲氧基·7·[3-(4-甲基-六氫°比嗪-1-基）-两氧基]啥琳·3-甲腈；（b) 〇1 5 〇重量％之一或多種黏合劑； 149415.doc 201113050 (c) 1-25重量％之一或多種填充劑；（d) 0.1-5重量％之一或多種崩解劑；（e) 0.1-5重量。/〇之一或多種潤濕劑（以組合物重量計）；及粒外組份（f) 1-25重量％之一或多種填充劑；及（g) 0.1 -5重量％之一或多種潤滑劑（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（&) 25-80重量％、或30-80重量％之4-(2,4-二氯-5-曱氧基-苯基胺基）-6-甲氧基-7-[3·(4-曱基-六氫吼°秦-1·基）-丙氧基]•喹淋-3-甲腈；（b) 0.5-5.0重量％之聚維銅（povidone); (c) 1-25重量％之微晶纖維素；〇.2-5重量％之交聯羧曱纖維素鈉，（e) 0.5-5重量％之泊洛沙姆（以組合物重量計）；及粒外組份（f) 1-25重量％之微晶纖維素；及（g) 0.5-5重量 %之硬脂酸鎂（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯-5-曱氧基-苯基胺基）-6-甲氧基-7-[3-(4-甲基-六氫。比嗪-1-基）_丙氧基喹啉-3-曱腈；（b) 約2重量％之聚維酮；（c)約6.5重量❶/〇之微晶纖維素；（d)約 2重量°/。之交聯羧曱纖維素鈉；（e)約3重量％之泊洛沙姆（以組合物重量計）；及粒外組份（f)約15重量％之微晶纖維素；及（g)約0.5重量％之硬脂酸鎂（以組合物重量計）。本發明提供包括以下之快速溶解性醫藥上可接受之組合物：粒内組份（a) 25-80重量％、或30-80重量％之4-(2,4-二氣-5-甲氧基-苯基胺基）-6-曱氧基-7-[3·(4-甲基-六氫吡嗪-1-基）-丙氧基]-喹啉-3-甲腈；（b) 0.5-5.0重量0/〇之一或多種黏合劑；（c) 1-25重量％之一或多種填充劑；（d) 〇_5-5重 149415.doc 201113050 量％之一或多種崩解劑；（e) 0.2-5重量％之一或多種潤濕劑 (以組合物重量計）；及粒外組份（f) 1 -25重量％之一或多種填充劑；（g) 0,5-5重量％之一或多種崩解劑；及（h) 0.5-5重量％之一或多種潤滑劑（以組合物重量計）。本發明提供包括以下之快速溶解性醫藥上可接受之組合物：粒内組份（a) 50-80重量％之4-(2,4-二氣-5-曱氧基-苯基胺基）-6-甲氧基-7-[3-(4-甲基-六氫°比嗪-1-基）-丙氧基]-喹啉-3-曱腈；（b) 0.5_5.0重量％之聚維酮；（c) 1-25重量％之微晶纖維素；（d) 0.5-5重量％之交聯敌甲纖維素鈉；（e) 0.2-5重量％之泊洛沙姆（以組合物重量計）；及粒外組份（f) 1-25重量％之微晶纖維素；（g) 〇.5_5重量％之交聯羧曱纖維素鈉；及（h)0_5-5重量％之硬脂酸鎂（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯-5-甲氧基·苯基胺基）-6-甲氧基-7-[3-(4-甲基-六氫η比嗪_ι_基）_丙氧基]_喹啉_3_曱腈；（b) 約2重量％之聚維酮；（c)約6.5重量％之微晶纖維素；（d)約 2重量％之交聯羧曱纖維素鈉；約3重量％之泊洛沙姆（以組合物重量計）；及粒外組份⑴約丨5重量❶/❶之微晶纖維素； (g)約2重量％之交聯羧甲纖維素鈉；及（h)約〇 5重量％之硬脂酸鎮（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内組份⑷25-80重量％、或30-80重量％之4-(2,4-二氯-5-甲氧基-笨基胺基）-6-甲氧基-7-[3-(4·曱基-六氫D比嗪-1_基）·丙氧基]-喹啉-3-曱腈；（b)聚維酮；微晶纖維素；（句〇2_5重 149415.doc 201113050 量％之交聯叛曱纖維素鈉；（e)泊洛沙姆（以組合物重量計）；及粒外組份（f)微晶纖維素；及（g)硬脂酸鎂。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯-5-曱氧基-苯基胺基）_6_甲氧基-7-[3·(4-曱基-六氫〇比<#-1-基）-丙氧基]-喧琳-3-曱腈；（b) 聚維酮；（c)微晶纖維素；（d)約2重量％之交聯缓甲纖維素鈉；（e)泊洛沙姆（以組合物重量計）；及粒外組份⑴微晶纖維素；及（g)硬脂酸鎂。本發明提供包括以下之快速溶解性醫藥上可接受之組合物：粒内組份（a) 50-80重量％之4-(2,4-二氣-5-甲氧基-苯基胺基）-6-曱氧基_7_[3_(4-甲基-六氫°比嗪-1-基）-丙氧基]-喹啉-3·甲腈；（b)聚維酮；（c)微晶纖維素；（d) 0.5-5重量％之交聯羧甲纖維素鈉；（e)泊洛沙姆（以組合物重量計）；及粒外組份（f)微晶纖維素；（g) 0.5-5重量％之交聯羧甲纖維素鈉；及（h)硬脂酸鎂（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯-5-曱氧基-笨基胺基）-6-曱氧基-7-[3-(4-曱基-六氫》比嗪-1-基）-丙氧基]-喹啉-3-甲腈；（b) 聚維酮；（c)微晶纖維素；（d)約2重量％之交聯羧甲纖維素鈉；（e)泊洛沙姆（以組合物重量計）；及粒外組份（f)微晶纖維素；（g)約2重量％之交聯羧甲纖維素鈉；及（h)硬脂酸鎂 (以组合物重量計）。本發明進一步提供醫藥上可接受之組合物（例如適用於兒科應用之組合物），其包括低至約25重量％、20重量。/〇、 149415.doc 201113050 或甚至15重量0/〇之4-(2,4-二氯-5-曱氧基-苯基胺基）_6甲氣基-7-[3-(4-甲基··六氫吡嗪_丨·基）_丙氧基]_喹啉_3曱腈及約0.25-5重量％、0.5-5重量％、1_3重量％、3重量％、2重量％或1重量％之交聯羧甲纖維素鈉（作為粒内組份）及約 0.25-5重量％、0.5-5重量。/〇、1-3重量％、3重量％、2重量％或1重量％之交聯羧甲纖維素鈉（作為粒外組份）、以及構成組合物剩餘部分之額外粒内及粒外組份（例如上文所述之彼等）。本發明進一步提供醫藥上可接受之組合物，其包括 4-(2,4-二氣-5-曱氧基·苯基胺基）_6_甲氧基_7_[3 (4_甲基-六氫吡嗪-1-基）-丙氧基卜喹啉_3_甲腈、及約〇 25_5重量％、〇.5-5重量％、1_3重量％、3重量％、2重量％或1重量％之交聯羧甲纖維素鈉（作為粒内組份）及約〇 25_5重量％、〇重置/ό 1 3重里/0、3重1；%、2重量％或1重量％之交聯敌甲纖維素鈉（作為粒外組份）、以及構成組合物剩餘部分之額外粒内及粒外組份（例如上文所述之彼等）。本發明另一實施例包含藉由壓製上述顆粒形成之錠劑或錠劑核心，其中該等核心視需要藉由習用方式進行塗覆，例如具有高達4%之聚合物膜塗層該聚合物包括習用塗覆聚合物。使用聚乙烯醇及PEG 335〇(〇padry red π及 Opadry Yellow Π)來施加實例性聚合物塗層。本發明亦提供包括4-(2,4-二氯-5-曱氧基-笨基胺基）-6-甲氧基-7-[3-(4-甲基-六氫吡嗪-丨_基）_丙氧基]_喹啉_3-曱腈之快速溶解性醫藥上可接受之固體組合物。 149415.doc 201113050 本發明亦提供製備包括4_(2,4·二氣_5_甲氧基·笨基胺基）6曱氧基-7-[3-(4·曱基_六氫π比唤_卜基）_丙氧基卜唾啉-3-曱腈之醫藥上可接受之穩定固體組合物的方法。窃本發明亦提供治療癌症之方法，其包括向個體投與有效里包括4-(2,4-二氣_5_甲氧基_笨基胺基）·6_甲氧基_7_[3_(4· 甲基-六氫吡嗪-1-基)_丙氧基]_喹啉_3_甲腈之醫藥上可接受之固體組合物。本發明之SKI-606固體組合物尤其可用於投與至人類或動物個體，包含（但不限於）兒科、少年、成年及老年個體。在第二實施例中，本發明提供包括以下物質作為粒内及/ 或粒外組份之醫藥上可接受之組合物：以組合物重量計， (a) 25-80重量％之4-(2,4-二氣_5_甲氧基_苯基胺基）_6_甲氧基-7-[3-(4-甲基-六氫吡嗪_1_基；)_丙氧基]_喹啉_3_甲腈；及 (b) 0.1 -20重量％之一或多種潤濕劑。本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a) 25-80重量％之4-(2,4-二氣-5-甲氧基-苯基胺基）-6-甲氧基-7-[3·(4-曱基-六氫0比嗪-1-基）-丙氧基]•喹啉-3-甲腈； (b) 0.5-5.0重量％之一或多種黏合劑；（c) 1-25重量％之一或多種填充劑；（d) 0.5-5重量％之一或多種崩解劑；（e) 0.2-5重量％之一或多種潤濕劑（以組合物重量計）；及粒外組份（f) 1-25重量％之一或多種填充劑；（g) 0.5-5.0重量％之一或多種潤濕劑；及（h) 〇·5·5重量％之一或多種潤滑劑 (以組合物重量計）。 149415.doc -11 - 201113050 本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a) 50-80重量％之4-(2,4-二氣_5·曱氧基-苯基胺基）_6_甲氧基-7-[3·(4-曱基-六氫吡嗪-丨·基）_丙氧基]_喹琳·3_曱腈； (b) 0.5-5.0重量％之聚維酮；（c)卜25重量％之微晶纖維素；（d) 0.5-5重量。/〇之交聚維酮；（e) 0.5-5重量％之聚氧乙烯山梨醇酐單油酸酯（Tween-80)TM(以組合物重量計）；及粒外組份（f) 1-25重量％之微晶纖維素；〇.5·5重量％之交聚維酮；及（h) 0_1-5重量％之硬脂酸鎂（以組合物重量計）。本發明k供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯_5_甲氧基_苯基胺基）_6_甲氧基-7-[3-(4-甲基-六氫。比嗪-卜基）_丙氧基]-喹啉_3·甲腈；（b) 約2重量％之聚維酮；（幻約195重量％之微晶纖維素；（d) 約3重量％之交聚維酮；（幻約丨重量％之聚氧乙烯山梨醇酐單油酸酯（Tween-80)™(以組合物重量計）；及粒外組份⑴ 約4重直％之微晶纖維素；（幻約丨重量％之交聚維酮及約 0.5重量％之硬脂酸鎂（以組合物重量計）。本發明提供包括以下之醫藥上可接受之組合物：粒内组份⑷約69重量％之4-(2,心二氣_5_甲氧基苯基胺基）冬甲氧基·7-[3·(4-甲基-六氫t秦小基）_丙氧基]•料_3_曱猜；⑻ 約2重量％之聚維酮；（c)约，〇 r & θ 里、勺19.5重量°/。之微晶纖維素；（d) 約3重量％之交聚維酮；（e)約1重量％之聚氧乙婦山梨醇酐單油酸醋（Tween·80严（以組合物重量計）；及粒外組份⑴ 約4重量％之微晶纖維素；(幻約1重量。/。之交聚維酮及(h)約 0.5重量％之硬脂酸鎂（以級合物重量計）。 149415.doc -12· 201113050 本發明提供包括以下之醫藥上可接受之組合物：粒内組份（a)約69重量％之4-(2,4-二氯-5-甲氧基-苯基胺基）-6-甲氧基-7-[3-(4-曱基-六氫吡嗪-丨-基）·丙氧基]_喹啉_3_甲腈；（b) 約2重量°/〇之聚維酮；（c)約丨9·5重量。/()之微晶纖維素；（句約1重量％之交聚維酮；（句約i重量％之聚氧乙烯山梨醇酐單油酸酯（Tween-80)™(以組合物重量計）；及粒外組份（f) 約4重量％之微晶纖維素；（g)約3重量％之交聚維酮及（h)約 0.5重量％之硬脂酸鎂（以組合物重量計）。本發明亦提供製備包括4-(2,4-二氣-5-甲氧基-苯基胺基）-6-曱氧基-7-[3-(4-曱基-六氫。比嗪_ι·基）_丙氧基]•喹啉-3-甲腈之醫藥上可接受之穩定固體組合物的方法。本發明亦提供治療癌症之方法，其包括向個體投與有效量的包括4-(2,4-二氣-5-甲氧基-苯基胺基）_6_曱氧基_7_[3_ (4-甲基-六氫η比唤-1-基）_丙氧基]_噎淋_3_甲腈之醫藥上可接受之固體組合物。本發明之SKI-606固體組合物尤其可用於投與至人類或動物個體，包含（但不限於）兒科、少年、成年及老年個體。【實施方式】 1 ·定 4 ·· 本文所用之「有效量」之化合物或醫藥上可接受之組合物可達成期望之治療及/或預防效應。在一些實施例中，「有效量」係至少最小量之化合物、或含有化合物之組合物’其足以治療一或多種與蛋白質酪胺酸激酶調節相關之 149415.doc -13- 201113050 病症.或病狀症狀。在某些實施例中，「有效量」之化合物、或含有化合物之組合物足以用於治療與異常酪胺酸激酶丈體相關之症狀、與異常酪胺酸激酶受體相關之疾病 (例如癌症，包含惡性及良性腫瘤生長）。本文所用之術語Γ個體」意指哺乳動物且包含人類及動物個體，例如家養動物（例如，馬、狗、貓等）。本文所用之術語「患有」（「suffer」或「suffering」）係指患者經診斷已患有、或懷疑患有之—或多種病狀。本文所用之術語「治療」（「treat」或「treating」）係指部分或完全減緩、抑制、延遲病症或病狀、或-或多種該病症或病狀症狀之發作，且預防、改善及/或減輕該病症或病狀 '或一或多種該病症或病狀症狀。類療法、 …療活性劑」4「活性劑」係指用於療法(例如，人獸醫療法）（包含預防及治療性處理）之物質（包含Biophysics and Molecular Biology, 1999, 71, 435-478). Various types of non-receptor tyrosine kinases are known in the art, including the Src family (eg, Src, Lyn, and Yes tyrosine kinases), the Abl family (eg, Abl and Arg), and the Jak family (eg, Jak 1 and Tyk 2). ). 3-cyanoquinoline compound 4-(2,4-dichloro-5-decyloxy-phenylamino)-6-methoxy-7-[3-(4-methyl-hexahydro. Qin-1-yl)-propoxy]-啥琳_3_carbonitrile is also known as SKI-606 or bosutinib, which has an intrinsic solubility of about 0.06 pg/mL at pH 8.0. Weak base. At pH less than 8, the solubility of compound SKI-606 increases exponentially with pH due to ionization. However, in the low pH aqueous solution (pH 3 and lower), it was observed that 3 _6〇6 was solved by hydrolysis, but the compound was relatively stable at pp5. Some of the problems with existing 3·cyanophthalocyanine solid formulations contain variable solubilization, which seems to depend on the particle size of the active pharmaceutical ingredient (Αρι). Contrary to the typical case, the smaller API (D9〇 is about 2 μm) in the pin formulation appears to hinder the dissolution under similar processing conditions for larger APIs (D9〇 about 4 μm). The result is that the dissolution specification cannot be reached. This is especially observed when using larger tablets (higher strength). In addition, it was observed that the formulation had accelerated dissolution characteristics at an earlier time point after aging/storage (smaller but significant shifting of aging after room temperature and accelerated conditions). The results are presented in two dissolution methods: the 0.1 N HCl method and the CTAB/pH 5 acetate method, and are further discussed below. The latter method was chosen to better demonstrate the dissolution profile over a period of up to 3 minutes. This was due to the discovery that the HC.1 N HC1 method released all drugs within the first 10-20 minutes. Therefore, it is desirable to provide a 3-cyanophthalocyanine compound for a patient (for example, '(2,4_dioxa-5-decyloxy-phenylamino)_6_decyloxy-7-[3-(4 Stable solid formulation of -mercapto-hexahydropyrazine-1-yl)-propoxy]-quinoline-3-indolecarbonitrile, which is unaffected by API particle size changes and compared during aging and storage stable. SUMMARY OF THE INVENTION The present invention discloses two innovative techniques: changing the type of disintegrant (and disintegrant ratio) to improve dissolution and stability; and using, for example, polyoxyethylene sorbitol liver monooleate (polysorbate/ Liquid surfactants such as polyoxyethylene sorbitan monooleate (Tween-80) instead of poloxamer (p〇i〇xamer) also improve solubility and stability at 149415.doc 201113050. In a first embodiment, the present invention provides a pharmaceutically acceptable solid composition of 3·cyanoquinoline, which comprises 4-(2,4-dimethoxy:phenylamino)-6- Oxy-7-[3-(4-methyl-hexahydro) than olfactory! · base) · propoxydipin-3-indene. In some implementations, such solid dimers are provided in the form of a bond. In some embodiments, the invention provides 4-(2,4-dichloro-methoxy-phenylamino)-6-methoxy-7-[3.(4-fluorenyl-hexahydro-β) Unit dosage form of 嘻_mercapto)propoxy]-quinolin-3-carbonitrile. The present invention provides a pharmaceutically acceptable composition comprising, as an intragranular component, (4) 180% by weight, or 3 〇·8 (% by weight) of 4-(2,4-dichloro). · 5-methoxy-phenylamino)·6曱oxy-7[3_(4-fluorenyl-hexahydropyrazine-1-yl)-propoxy]•quinoline-3-carbonitrile; And (b) cm-20% by weight of one or more wetting agents. The present invention provides a pharmaceutically acceptable composition comprising, as an intragranular component, (4) 25-80% by weight, or 30_80% by weight of 4-(2,4-dichloro·5·methoxy-phenylamino)_6_methoxy-7_[3_(4_ fluorenylhydropyridazinyl)-propoxy]-quin And oxo-3-indene nitrile; and (b) 0.1-20 hydrazine/hydrazine or a plurality of wetting agents, wherein the intragranular component of the composition further accounts for 4'' and <82.5% by weight of & The outer component comprises 丨75 weight 〇/〇 of the composition. The present invention provides a pharmaceutically acceptable composition comprising the following: intragranular group injury (hook 25-80 weight 〇/〇, or 30-80 weight 〇 /0 4-(2,4-dioxa-5-methoxy-phenylamino)·6-methoxy·7·[3-(4-methyl-hexahydropyrazine-1 -yl)-dioxy]phthalene-3-carbonitrile; (b) 〇1 5 〇% by weight of one or more binders; 149415.doc 201113050 (c) 1-25% by weight of one or more fillers (d) 0.1 to 5% by weight of one or more disintegrants; (e) 0.1 to 5 parts by weight per one or more wetting agents (by weight of the composition); and extragranular components (f) 1 to 25% by weight of one or more fillers; and (g) 0.1 to 5% by weight of one or more lubricants (by weight of the composition). The present invention provides a pharmaceutically acceptable composition comprising: Internal component (&) 25-80% by weight, or 30-80% by weight of 4-(2,4-dichloro-5-decyloxy-phenylamino)-6-methoxy-7- [3.(4-Mercapto-hexahydroindole~-l-yl)-propoxy]-quinoline-3-carbonitrile; (b) 0.5-5.0% by weight of povidone; c) 1 to 25% by weight of microcrystalline cellulose; 2 to 5% by weight of croscarmellose sodium, (e) 0.5 to 5% by weight of poloxamer (by weight of the composition); And extragranular component (f) from 1 to 25% by weight of microcrystalline cellulose; and (g) from 0.5 to 5% by weight of magnesium stearate (by weight of the composition). The following provides a pharmaceutically acceptable composition comprising: intragranular component (a) about 69% by weight of 4-(2,4-dichloro-5-decyloxy-phenylamino)-6-A Oxy-7-[3-(4-methyl-hexahydro.pyrazine-1-yl)-propoxyquinoline-3-indoleonitrile; (b) about 2% by weight of povidone; (c ) about 6.5 weight ❶ / 〇 of microcrystalline cellulose; (d) about 2 weight ° /. Cross-linked carboxymethylcellulose sodium; (e) about 3% by weight of poloxamer (by weight of the composition); and extragranular component (f) about 15% by weight of microcrystalline cellulose; and (g ) about 0.5% by weight of magnesium stearate (by weight of the composition). The present invention provides a pharmaceutically acceptable composition comprising the following rapid solubility: intragranular component (a) 25-80% by weight, or 30-80% by weight 4-(2,4-digas-5-A Oxy-phenylamino)-6-methoxy-7-[3.(4-methyl-hexahydropyrazin-1-yl)-propoxy]-quinoline-3-carbonitrile; b) one or more of 0.5-5.0 weight 0/〇 one or more binders; (c) 1-25% by weight of one or more fillers; (d) 〇_5-5 weight 149415.doc 201113050 a disintegrant; (e) 0.2 to 5% by weight of one or more wetting agents (by weight of the composition); and an extragranular component (f) 1 to 25% by weight of one or more fillers; (g) 0, 5-5 wt% one or more disintegrants; and (h) 0.5-5 wt% one or more lubricants (by weight of the composition). The present invention provides a pharmaceutically acceptable composition comprising the following rapid solubility: intragranular component (a) 50-80% by weight of 4-(2,4-dioxa-5-decyloxy-phenylamino group) - 6-methoxy-7-[3-(4-methyl-hexahydropyrazine-1-yl)-propoxy]-quinoline-3-indoleonitrile; (b) 0.5_5.0 % by weight of povidone; (c) 1-25% by weight of microcrystalline cellulose; (d) 0.5-5 wt% of crosslinked terephthalic acid sodium; (e) 0.2-5 wt% of poloxa (by weight of the composition); and extragranular component (f) 1-25% by weight of microcrystalline cellulose; (g) 5.5_5% by weight of croscarmellose sodium; and (h) 0_5 - 5% by weight of magnesium stearate (by weight of the composition). The present invention provides a pharmaceutically acceptable composition comprising the following components: intragranular component (a) about 69% by weight of 4-(2,4-dichloro-5-methoxy-phenylamino)-6- Methoxy-7-[3-(4-methyl-hexahydroηpyrazine_ι_yl)-propoxy]_quinoline_3_phthalonitrile; (b) about 2% by weight of povidone (c) about 6.5% by weight of microcrystalline cellulose; (d) about 2% by weight of croscarmellose sodium; about 3% by weight of poloxamer (by weight of the composition); Component (1) about 5 parts by weight of lanthanum/microcrystalline cellulose; (g) about 2% by weight of croscarmellose sodium; and (h) about 5% by weight of stearic acid (by composition) Weight meter). The present invention provides a pharmaceutically acceptable composition comprising: intragranular component (4) 25-80% by weight, or 30-80% by weight of 4-(2,4-dichloro-5-methoxy-stupylamine (6) methoxy-7-[3-(4. fluorenyl-hexahydro D-pyrazine-1_yl)-propoxy]-quinoline-3-indoleonitrile; (b) povidone Microcrystalline cellulose; (Sentence 2_5 weighs 149415.doc 201113050 % by weight of cross-linked sputum cellulose sodium; (e) poloxamer (by weight of the composition); and extragranular component (f) micro Crystalline cellulose; and (g) magnesium stearate. The present invention provides a pharmaceutically acceptable composition comprising: intragranular component (a) about 69% by weight of 4-(2,4-dichloro-5) -曱oxy-phenylamino)_6_methoxy-7-[3·(4-mercapto-hexahydroindole ratio <#-1-yl)-propoxy]-喧琳-3- (b) povidone; (c) microcrystalline cellulose; (d) about 2% by weight of crosslinked sodium carboxymethylcellulose; (e) poloxamer (by weight of the composition); Extragranular component (1) microcrystalline cellulose; and (g) magnesium stearate. The present invention provides a pharmaceutically acceptable composition comprising the following rapid solubility: intragranular component (a) 50-80% by weight of 4 -(2, 4-diox-5-methoxy-phenylamino)-6-decyloxy_7_[3_(4-methyl-hexahydropyrazine-1-yl)-propoxy]-quinoline -3. carbonitrile; (b) povidone; (c) microcrystalline cellulose; (d) 0.5 to 5% by weight of croscarmellose sodium; (e) poloxamer (by weight of the composition) And extragranular component (f) microcrystalline cellulose; (g) 0.5 to 5% by weight of croscarmellose sodium; and (h) magnesium stearate (by weight of the composition). The invention provides a pharmaceutically acceptable composition comprising: intragranular component (a) about 69% by weight of 4-(2,4-dichloro-5-decyloxy-phenylamino)-6-oxime Oxy-7-[3-(4-mercapto-hexahydro)pyrazine-1-yl)-propoxy]-quinoline-3-carbonitrile; (b) povidone; (c) microcrystal Cellulose; (d) about 2% by weight of croscarmellose sodium; (e) poloxamer (by weight of the composition); and extragranular component (f) microcrystalline cellulose; (g) About 2% by weight of croscarmellose sodium; and (h) magnesium stearate (by weight of the composition). The invention further provides pharmaceutically acceptable compositions (for example, compositions suitable for pediatric applications) , Including as low as about 25% by weight, 20% by weight, /〇, 149415.doc 201113050 or even 15% by weight of 4- 4-(2,4-dichloro-5-decyloxy-phenylamino)_6-methyl -7-[3-(4-methyl.hexahydropyrazine-indolyl)-propoxy]-quinoline-3 tricarbonitrile and about 0.25-5 wt%, 0.5-5 wt%, 1_3 5% by weight, 3% by weight, 2% by weight or 1% by weight of croscarmellose sodium (as intragranular component) and about 0.25 to 5% by weight, 0.5 to 5 parts by weight. /〇, 1-3% by weight, 3% by weight, 2% by weight or 1% by weight of croscarmellose sodium (as an extragranular component), and additional intragranular and extragranular groups constituting the remainder of the composition Parts (such as those described above). The present invention further provides a pharmaceutically acceptable composition comprising 4-(2,4-dioxa-5-methoxy-phenylamino)-6-methoxy-7-[3 (4-methyl- Hexahydropyrazin-1-yl)-propoxybuquinoline_3_carbonitrile, and about 25-5 wt%, 〇5-5 wt%, 1-3 wt%, 3% wt%, 2 wt% or 1 5% by weight of croscarmellose sodium (as intragranular component) and about 25_5% by weight, 〇reset / ό 1 3 cc / 0, 3 weight 1; %, 2% by weight or 1% by weight Sodium terephthalate sodium (as an extragranular component), and additional intragranular and extragranular components (such as those described above) that make up the remainder of the composition. Another embodiment of the invention comprises a lozenge or lozenge core formed by compressing the above-described granules, wherein the cores are coated by conventional means, for example, having a polymer film coating of up to 4%, the polymer comprising Conventional coated polymers. An exemplary polymer coating was applied using polyvinyl alcohol and PEG 335(R) (〇padry red π and Opadry Yellow®). The invention also provides 4-(2,4-dichloro-5-decyloxy-phenylamino)-6-methoxy-7-[3-(4-methyl-hexahydropyrazine-oxime) Rapid solubility of _yl)-propoxy]_quinoline-3-carbonitrile is a pharmaceutically acceptable solid composition. 149415.doc 201113050 The present invention also provides a preparation comprising 4-(2,4·dioxa-5-methoxy-phenylamino)6-methoxy-7-[3-(4.mercapto-hexahydro-pi ratio) A method of pharmaceutically acceptable stable solid compositions of acetoin-propoxysporin-3-indene. The invention also provides a method of treating cancer comprising administering 4-(2,4-dioxa-5-methoxy-phenylamino)-6_methoxy_7_[3_ A pharmaceutically acceptable solid composition of (4. methyl-hexahydropyrazin-1-yl)-propoxy]-quinoline-3-carbonitrile. The SKI-606 solid compositions of the present invention are especially useful for administration to human or animal subjects including, but not limited to, pediatric, juvenile, adult and aged individuals. In a second embodiment, the invention provides a pharmaceutically acceptable composition comprising, as an intragranular and/or extragranular component, (a) 25-80% by weight of 4-(by weight of the composition) 2,4-digas_5_methoxy-phenylamino)_6-methoxy-7-[3-(4-methyl-hexahydropyrazine-1-yl;)-propoxy] _ quinoline_3_carbonitrile; and (b) 0.1-20% by weight of one or more wetting agents. The present invention provides a pharmaceutically acceptable composition comprising: intragranular component (a) 25-80% by weight of 4-(2,4-dioxa-5-methoxy-phenylamino)-6 -methoxy-7-[3.(4-indolyl-hexahydro 0-pyridin-1-yl)-propoxy]•quinoline-3-carbonitrile; (b) one of 0.5-5.0% by weight Or a plurality of binders; (c) 1-25% by weight of one or more fillers; (d) 0.5 to 5% by weight of one or more disintegrants; (e) 0.2 to 5% by weight of one or more wetting agents Agent (by weight of the composition); and extragranular component (f) 1-25% by weight of one or more fillers; (g) 0.5-5.0% by weight of one or more wetting agents; and (h) 〇 • 5% by weight of one or more lubricants (by weight of the composition). 149415.doc -11 - 201113050 The present invention provides a pharmaceutically acceptable composition comprising the following: intragranular component (a) 50-80% by weight of 4-(2,4-dioxa_5·decyloxy- Phenylamino)_6_methoxy-7-[3·(4-indolyl-hexahydropyrazine-fluorenyl)-propoxy]-quinoline·3_indene nitrile; (b) 0.5- 5.0% by weight of povidone; (c) 25% by weight of microcrystalline cellulose; (d) 0.5-5 by weight. (e) 0.5 to 5% by weight of polyoxyethylene sorbitan monooleate (Tween-80) TM (by weight of the composition); and extragranular component (f) 1 -25% by weight of microcrystalline cellulose; 5% to 5% by weight of crospovidone; and (h) 0 to 1-5% by weight of magnesium stearate (by weight of the composition). The present invention k provides the following pharmaceutically acceptable composition: intragranular component (a) about 69% by weight of 4-(2,4-dichloro-5-methoxy-phenylamino)_6_ Methoxy-7-[3-(4-methyl-hexahydro.pyrazine-buyl)-propoxy]-quinoline-3 carbonitrile; (b) about 2% by weight of povidone; (approximately 195% by weight of microcrystalline cellulose; (d) about 3% by weight of crospovidone; (% by weight of polyoxyethylene sorbitan monooleate (Tween-80)TM The weight of the composition); and the extragranular component (1) about 4% by weight of microcrystalline cellulose; (approximately 10% by weight of crospovidone and about 0.5% by weight of magnesium stearate (by weight of the composition) The present invention provides a pharmaceutically acceptable composition comprising the following: intragranular component (4) about 69% by weight of 4-(2, pentane _5-methoxyphenylamino) methoxymethoxy 7-[3·(4-Methyl-hexahydrot-methylglycolyl)-propoxy]•material_3_曱 guess; (8) about 2% by weight of povidone; (c) about 〇r & θ , a spoon of 19.5 weight% microcrystalline cellulose; (d) about 3% by weight of crospovidone; (e) about 1% by weight of polyoxymethylene sorbitan Oleic acid vinegar (Tween·80 strict (by weight of the composition); and extragranular component (1) about 4% by weight of microcrystalline cellulose; (approximately 1 weight of crospovidone and (h) about 0.5% by weight of magnesium stearate (by weight of the compound). 149415.doc -12· 201113050 The present invention provides a pharmaceutically acceptable composition comprising the following: intragranular component (a) about 69% by weight 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-indolyl-hexahydropyrazine-fluorenyl)-propane Oxy]_quinoline_3_carbonitrile; (b) about 2 wt/min of povidone; (c) about 9.5 wt./() of microcrystalline cellulose; % crospovidone; (about 1% by weight of polyoxyethylene sorbitan monooleate (Tween-80) TM (by weight of the composition); and extragranular component (f) about 4% by weight Microcrystalline cellulose; (g) about 3% by weight of crospovidone and (h) about 0.5% by weight of magnesium stearate (by weight of the composition). The invention also provides for the preparation of 4-(2, 4-diox-5-methoxy-phenylamino)-6-decyloxy-7-[3-(4-mercapto-hexahydro.pyrazine_ι·yl)-propoxy]• Quinoline-3-carbonitrile A pharmaceutically acceptable method of stabilizing a solid composition. The invention also provides a method of treating cancer comprising administering to a subject an effective amount of 4-(2,4-dioxa-5-methoxy-phenylamine) A pharmaceutically acceptable solid composition of the group _6_decyloxy_7_[3_(4-methyl-hexahydron-l-l-yl)-propoxy]-indole_3_carbonitrile. The SKI-606 solid compositions of the present invention are especially useful for administration to human or animal subjects including, but not limited to, pediatric, juvenile, adult, and elderly individuals. [Embodiment] 1 · 定 4 · · An "effective amount" of a compound or a pharmaceutically acceptable composition as used herein may achieve the desired therapeutic and/or prophylactic effect. In some embodiments, an "effective amount" is at least a minimum amount of a compound, or a composition comprising a compound that is sufficient to treat one or more conditions associated with protein tyrosine kinase regulation 149415.doc -13-201113050. Symptoms. In certain embodiments, an "effective amount" of a compound, or a composition comprising a compound, is sufficient to treat a condition associated with an abnormal tyrosine kinase, a disease associated with an abnormal tyrosine kinase receptor (eg, cancer) Contains malignant and benign tumor growth). As used herein, the term "individual" means a mammal and includes both human and animal individuals, such as domestic animals (e.g., horses, dogs, cats, etc.). The term "suffer" or "suffering" as used herein refers to a patient who has been diagnosed with, or suspected of having, a plurality of conditions. The term "treat" or "treating" as used herein refers to the partial or complete alleviation, inhibition, delay of a condition or condition, or - or the onset of a plurality of symptoms of the condition or condition, and prevention, amelioration and/or Or alleviating the condition or condition ' or one or more symptoms of the condition or condition. Class therapy, "active agent" 4 "active agent" means a substance used in therapy (for example, human veterinary therapy) (including prophylactic and therapeutic treatment) (including

生物活合物、蛋白、接之小分子、糖蛋白、酸、核苷、寡核茌醢、敗、核苦、寡核普酸、反義募他命。治療活性劑包括用作藥減輕或改善疾病、病狀 '或病調配物中之治療活性劑係類鴉片止痛化合物、及諸如此類。活性劑之化合物。治疼 H94l5.doc •14- 201113050 合物之效少錢仙來增效的化合物。乐—化合物之效應或功本文所用之表達「單位劑型」係指本發明調配物的物理分散單位於一療個體之 ^ AL. ^ …、而’應理解’本發明组口勿之…日用量應由主治醫師在 . 定。住一姓〜、 Μ。理的醫學判斷範圍内確辛，心人疋固體或有機體之具體有效劑量取決於多種因所治療病症及該病症之嚴重㈣；所㈣定之活性；所用特定組合物；個體之年齡、體重』體健康m別聽食；利料料狀投與時間、及排泄速^治療持續時間；與所用特定化合物組合或同時使用之藥物及/額外治療劑；及醫學技術中熟知之類似因素。簡g之’「&燥摻和」材料係在填充膠囊或壓製旋劑之 μ其以物理方式摻和至_ <。參見Handb〇〇k 〇f Pharmaceutical Granuiation Techn〇1〇gy，1997, DiHp parikh， Marcel Dekker公司，ISBN 0-8247-9882-1，第 309 頁。Biological organisms, proteins, small molecules, glycoproteins, acids, nucleosides, oligonuclears, dysfunction, nuclear bitterness, oligonucleotides, antisense recruitment. Therapeutic active agents include use as a medicament to alleviate or ameliorate a disease, a condition, or a therapeutically active agent in a disease formulation, such as a cider tablet analgesic compound, and the like. A compound of an active agent. Treatment of pain H94l5.doc •14- 201113050 The compound has less effect on the compound. The expression "unit dosage form" as used herein refers to the physical dispersion unit of the formulation of the present invention in a single individual. AL. ^ ..., and 'should understand' that the group of the present invention does not use ... daily dosage It should be determined by the attending physician. Live a surname ~, Μ. The specific effective dose of a healthy person or a solid body depends on a variety of conditions and the severity of the condition (4); (4) the activity specified; the specific composition used; the age and weight of the individual Health m don't listen; time to dose, and speed of excretion ^ duration of treatment; drugs and/or additional therapeutic agents used in combination or concurrent with the particular compound used; and similar factors well known in the medical arts. The "& dry blend" material is physically filled to <<>> See Handb〇〇k 〇f Pharmaceutical Granuiation Techn〇1〇gy, 1997, DiHp parikh, Marcel Dekker, ISBN 0-8247-9882-1, page 309.

在乾法造粒（擊壓或輥壓）中，摻和粒内材料以備用於擊壓或輥壓。將材料研磨並與粒外材料摻和，隨後填充膠囊或壓製鍵劑2 0。濕法造粒需要摻和粒内材料。在使用或不使用黏合劑之情形下’對摻合物及水實施濕法造粒（使用高剪切造粒機、低剪切造粒機）並乾燥（使用高達i 〇〇°C之溫度）。將材料研磨並與粒外材料掺和，隨後填充膠囊或壓製鍵劑。參見25 Handbook of Pharmaceutical Granulation Technology，1997，Dilip Parikh，Marcel Dekker公司，ISBN 149415.doc -15- 201113050 0-8247-9882-1 ，第 338-368頁。 2·醫藥上可接受之組合物及調配物：在某些實施例中，本發明之醫藥上可接受之組合物包括 SKI-606及一或多種其他賦形劑，例如，一或多種黏合劑、載劑、黏度改良劑及懸浮劑、潤濕劑、潤濕劑、甜味劑、pH改良劑、矯味劑、防腐劑及其組合。熟習此項技術者應易於瞭解，所列示特定組份之種類並不意欲具有限制性；在一些情形中，特定組份可適當地具有一種以上種類。同樣，應瞭解，在特定調配物之背景中，端視（例如）成份量及/或是否存在其他成份及/或活性化合物，相同組份有時可實施不同功能，或可實施一種以上功能。在某些貫施例中’本發明提供包括以下之醫藥上可接受之固體組合物：4-(2,4-二氯_5_曱氧基_苯基胺基）_6_甲氧基_7_[3-(4_甲基·六氫吡嗪-1-基）-丙氧基]-喹啉-3-甲腈（亦稱作SKI-606)。SKI-606以及SKI-606之製備方法闡述於中美國專利第6,297,258號中，如美國專利第7,297,795號中所述。SKI-606具有下列結構： c丨丨In dry granulation (squeezing or rolling), the intragranular material is blended for use in crushing or rolling. The material is ground and blended with the extragranular material, followed by filling the capsule or pressing the bonding agent 20 . Wet granulation requires the incorporation of intragranular materials. Wet granulation of the blend and water (using a high shear granulator, low shear granulator) and drying (using temperatures up to i 〇〇 ° C with or without binder) ). The material is ground and blended with the extragranular material, which is then filled or encapsulated. See 25 Handbook of Pharmaceutical Granulation Technology, 1997, Dilip Parikh, Marcel Dekker, Inc. 149415.doc -15-201113050 0-8247-9882-1, pp. 338-368. 2. Pharmaceutically Acceptable Compositions and Formulations: In certain embodiments, the pharmaceutically acceptable compositions of the present invention comprise SKI-606 and one or more other excipients, for example, one or more binders , carriers, viscosity improvers and suspending agents, wetting agents, wetting agents, sweeteners, pH improvers, flavoring agents, preservatives, and combinations thereof. It will be readily understood by those skilled in the art that the particular types of components listed are not intended to be limiting; in some instances, the particular components may suitably have more than one species. Also, it is to be understood that in the context of a particular formulation, the amount of component(s) and/or the presence or absence of other components and/or active compounds may be carried out in the context of a particular formulation, and the same components may sometimes perform different functions or may perform more than one function. In certain embodiments, the invention provides a pharmaceutically acceptable solid composition comprising 4-(2,4-dichloro-5-nonyloxy-phenylamino)-6-methoxy 7-[3-(4-Methylhexahydropyrazin-1-yl)-propoxy]-quinoline-3-carbonitrile (also known as SKI-606). The preparation of SKI-606 and SKI-606 is described in U.S. Patent No. 6,297,258, issued to U.S. Patent No. 7,297,795. SKI-606 has the following structure: c丨丨

SKI-606單水合物且分離為單水合物形式。3-氰基喹啉化合物4-(2,4-二氣·5- 149415.doc 201113050 甲，基·苯基胺基）·6_甲氧基·Η3.(4-甲基-六氫终氧土]圭琳·3-甲腈係在8 〇之阳下固有溶解度為約〇〇6 Kg/mL之弱鹼。在ρΗ小於8時化合物祕之溶解度由於電離而隨ΡΗ降低指數性增加。然而’在低pH水溶液中觀察到ski.經由水解發生分解，但該化合物在ρΗ高於5 時相對穩定，此時4胺基喹啉基團並未電離。在某些實施例中，本發明3耵_6〇6調配物可消除關於3· 氰基喹啉固體調配物之一或多個問題，該等問題包含：溶解作用有所變化（此似乎取決於粒徑），在儲存時加速溶解，及在儲存時穩定性受限。本發明之交聯羧甲纖維素 SKI-606調配物顯示，崩解時間（約2_7分鐘）快於使用習用崩解劑（例如交聚維酮’崩解時間為約18_2〇分鐘）之可比 SKI-606調配物。在某些實施例中，本發明SKI-606調配物包括塗覆膜之 SKI-606調配物’其係藉由高剪切濕法造粒或盤式塗覆製得。在其他實施例中’塗覆膜之SKI-606錠劑調配物係藉由其他習用塗覆技術製得。比較使用習用崩解劑交聚維酮及使用交聯羧甲纖維素鈉之SKI-606調配物的崩解時間且匯總於表2中。此情形中之粒内崩解劑保持恆定於3 % w/w。兩種調配物具有顯著不同之崩解時間，例如’ 2%粒外（EG) SKI-606/CCS調配物之錠劑崩解時間（〇丁）僅為3.5分鐘，與之相比，80-606/€?¥調配物之DT為22分鐘。此外，亦觀察到，對於所有SKI-606/CPV調配物，錠劑DT皆高度取決於錠劑硬度，而在 H9415.doc 17 201113050 SKI-606/CCS調配物中未觀察到該依賴性。舉例而言，即使對於3% IG及2% EG SKI-606/CPV調配物，低硬度錠劑與高硬度錠劑之DT時間相差14分鐘（範圍），而SKI-606/CCS調配物僅相差3.5分鐘。此觀察結果表明，SKI-606/CCS調配物在錠劑硬度方面較為穩定，此係本發明 SKI-606調配物在錠劑可製造性特性方面之顯著改善。亦在0.1 N HC1中溶解本發明SKI-606調配物之錠劑（參見圖1)，其顯示在崩解劑濃度低於SKI-606/CPV調配物所用濃度下，SKI-606/CCS調配物之錠劑在10及15分鐘時之溶解較快。此外，數據亦顯示，較低黏合劑濃度可尤其在較早時間點時增強溶解作用。在某些實施例中，本發明SKI-606調配物中提供相似溶解結果之交聯羧甲纖維素鈉（CCS)的量如下： 1. 0-2% w/w粒内濃度 2. 1-3% w/w粒外濃度 3·黏合劑（聚維酮濃度）亦可在1-2% w/w之間有所變化。在某些實施例中，本發明SKI-606調配物中粒内組份與粒外組份之比率在3 :1至2:2之間有所變化。在某些實施例中，在本發明SKI-606調配物之製錠期間，將一種粒内（IG)組份（包括微晶纖維素（MCC)之填充劑）自粒内部分轉移至粒外（EG)組份以有利於獲得較快崩解時間。以SKI-606調配物之重量計，粒外填充劑組份之量自4重量％增至15重量％。SKI-606 monohydrate and isolated as a monohydrate form. 3-cyanoquinoline compound 4-(2,4-digas·5- 149415.doc 201113050 A, phenyl-phenylamino)·6-methoxy·Η3. (4-methyl-hexahydrogen Oxygen soil] Guerin·3-carbonitrile is a weak base with an intrinsic solubility of about 6 Kg/mL under the cation of 8 。. When ρΗ is less than 8, the solubility of the compound secret decreases exponentially with enthalpy due to ionization. However, it was observed that ski in a low pH aqueous solution was decomposed via hydrolysis, but the compound was relatively stable at pH Η above 5, at which point the 4-aminoquinoline group was not ionized. In certain embodiments, the invention The 3耵_6〇6 formulation eliminates one or more of the problems associated with the solid formulation of 3·cyanoquinolines, which include: a change in solubility (which seems to depend on particle size), which accelerates during storage Dissolution, and stability when stored. The croscarmellose SKI-606 formulation of the present invention shows that the disintegration time (about 2-7 minutes) is faster than the use of conventional disintegrants (such as crospovidones) A comparable SKI-606 formulation having a solution time of about 18-2 〇 minutes. In certain embodiments, the SKI-606 formulation of the present invention comprises a coated film S The KI-606 formulation' is made by high shear wet granulation or disc coating. In other embodiments, the 'coated SKI-606 tablet formulation is by other conventional coating techniques. The disintegration time of the formulation of the conventional disintegrating agent crospovidone and the SKI-606 formulation using croscarmellose sodium was compared and summarized in Table 2. In this case, the intragranular disintegrant remained constant. At 3 % w/w, the two formulations have significantly different disintegration times, such as '2% extragranular (EG) SKI-606/CCS formulation, which has a tablet disintegration time (Kentin) of only 3.5 minutes. In contrast, the DT of the 80-606/€?¥ formulation was 22 minutes. In addition, it was also observed that for all SKI-606/CPV formulations, the tablet DT was highly dependent on the tablet hardness, while at H9415. .doc 17 201113050 This dependence is not observed in the SKI-606/CCS formulation. For example, even for 3% IG and 2% EG SKI-606/CPV formulations, low hardness tablets and high hardness tablets The DT time differed by 14 minutes (range), while the SKI-606/CCS formulations differed by only 3.5 minutes. This observation shows that the SKI-606/CCS formulation is in terms of tablet hardness. For stability, this is a significant improvement in the manufacturability properties of the SKI-606 formulation of the present invention. The tablet of the SKI-606 formulation of the present invention is also dissolved in 0.1 N HCl (see Figure 1), which is shown in The concentration of the disintegrant is lower than that of the SKI-606/CPV formulation, and the tablet of the SKI-606/CCS formulation dissolves faster at 10 and 15 minutes. In addition, the data also shows that the lower binder concentration can be Especially at earlier points in time, the dissolution is enhanced. In certain embodiments, the amount of croscarmellose sodium (CCS) that provides similar dissolution results in the SKI-606 formulations of the invention is as follows: 1. 0-2% w/w intragranular concentration 2. 1- 3% w/w extragranular concentration 3·adhesive (povidone concentration) may also vary between 1-2% w/w. In certain embodiments, the ratio of intragranular component to extragranular component in the SKI-606 formulation of the invention varies from 3:1 to 2:2. In certain embodiments, an intragranular (IG) component, including a filler of microcrystalline cellulose (MCC), is transferred from the intragranular portion to the extragranular portion during the tableting of the SKI-606 formulation of the present invention. The (EG) component is advantageous for obtaining a faster disintegration time. The amount of the extragranular filler component was increased from 4% by weight to 15% by weight based on the weight of the SKI-606 formulation.

在某些實施例中，將EG組份中之MCC等級自Avicel PH 149415.doc •18· 201113050 101™變為Avicel PH 102頂以促進錠劑摻合物之流動。在某些實施例中，與經常觀察到Αρι之粒徑減小通常導致溶解速率增加相反，據觀察，對於SKI 606調配物而 5，在使用與具有較高D90 API粒徑之調配物相同之方式處理時，減小API粒徑往往會降低調配物之溶解作用。因此，據觀察，API粒徑愈低則溶解速率愈慢，且Αρι粒徑愈鬲則溶解速率愈快，如圖6中所匯總。為使溶解作用最大化，現有調配物可能使用之一種方式係增加諸如SKI-606等藥物之粒徑。為減慢溶解，實施方式係使用較低粒徑之API。在某些Λ施例中，在投與至人類或動物個體時，並不改變本發明SKI-6G6調配物中之泊洛沙姆濃度以維持活體内效應。在某二μ %例中，本發明調配物可含有一或多種非速碑、制f ㈣或塗層。非速率控制性層在調配物十之位童並不重要。舉例而言，非速率控制性層可位於至少一個相 ^與腸溶塗層或速率㈣性結構之間。或者，非速率控制性層可包圍或塗覆腸溶塗層或速率控制性機構制性届？Γ rK ^ 層了由一或多種聚合物以及業内已知之其他成份（例旦不限於增塑劑、顏料/遮光劑等）構成。可用聚合物之含(但不限於)羥丙基甲基纖维素、羥丙基纖維素、、土纖維素、乙基纖維素、％乙烯醇、及聚乙二醇。可用之實例包含（但限於）聚乙二醇、甘油、三醋汀、捧豕酉-乙酯、鄰苯二甲酸二乙酯及礦物油。可用顏料/遮 H9415.doc 201113050 光劑之實例包含（但不限於）水溶性染料、顏料、及天然產物。在某些實施例中，本發明調配物亦可包含至少—個腸溶塗層。任一腸溶塗層冑可用於本發明中，包含（但不限於）以下物質之溶液或分散液：曱基丙烯酸與甲基丙烯酸酿共聚物、乙酸鄰苯二甲酸纖維素、鄰苯二甲酸羥丙基曱基纖維素、乙酸琥站酸羥丙基甲基纖維素、乙酸鄰苯二曱酸聚乙烯基酯、丙烯酸乙酯/甲基丙烯酸共聚物、乙酸偏苯三酸纖維素、蟲膠及其组合。此外，用於本發明調配物中之腸溶塗層可以單層或多層形式形成。塗層厚度可容易地由彼等熟習此項技術者確實，但必須足以在酸性胃環境中保護調配物。在某些實施例中’基於使用交聯羧曱纖維素鈉代替一種習用崩解劑交聚維酮’發明了 SKI-606之醫藥上可接受之固體組合物，其可出人意料地改善SKI-606調配物之穩定性並得到均勻溶解速率（參見表1及圖丨_3)。潤濕劑在業内係眾所周知且通常可促進藥物釋放及吸收。實例性潤濕劑包含泊洛沙姆、聚氧乙烯醚、聚氧乙烯山梨醇酐脂肪酸酯、聚氧乙烯脂肪酸酯、聚已二醇脂肪酸 S旨、聚氧乙烯氫化蓖麻油、聚氧乙稀炫基趟、聚山梨醇酯、鯨蠟醇、甘油脂肪酸酯（例如，三醋汀、甘油單硬脂酸酯及諸如此類）、聚氧甲烯硬脂酸酯、月桂基硫酸鈉、山梨醇酐脂肪酸酯、蔗糖脂肪酸酯、笨紮氣銨 (benzalkonium chloride)、聚乙氧基化蓖麻油、及多庫醋 149415.doc •20- 201113050 鈉、及諸如此類、及其組合。在一些實施例中，潤濕劑包含（但不限於）（例如）聚山梨醇酯8〇TM、甘油、聚山梨醇酯 65™、聚山梨醇酯60™ USP、聚山梨醇酯40™ USP、聚山梨醇酯20™ USP、辛苯聚醇、壬苯聚醇_1〇〜usp、泊洛沙姆235™、泊洛沙姆188™ usp。在一些實施例中，以調配物之總重量計，所提供潤濕劑佔約〇1重量％至約5重量 %、約1.0重量。/〇至約4重量％、或約3 〇重量％。在某些實施例中，潤濕劑係泊洛沙姆，其包含（但不限於）例如泊洛沙姆 188TM (Lutrol F-68)。業内已知適宜黏合劑（亦稱作「稀釋劑」及/或「填充劑」）。舉例而δ ’適宜黏合劑及填充劑包含但不限於澱叙、糊精、蔗糖、山梨醇、糖精鈉、乙醯胺基磺酸鉀、木糖醇、天冬甜素 '甘露醇、澱粉、ρνρ(聚乙烯吡咯啶酮）低为子里HPC(羥丙基纖維素）、微晶纖維素（MCC)、低分子量HPMC(羥丙基甲基纖維素）、低分子量羧甲基纖維素、乙基纖維素、藻酸鹽、明膠、聚氧乙烯' 阿拉伯膠、糊精、蔗糖、矽酸鎂鋁、及聚曱基丙烯酸酯。填充劑匕3選自由以下組成之群之試劑：微晶纖維素、澱粉、拉克替醇（lacutol)、乳糖、適宜無機鈣鹽、蔗糖、葡萄糖、硌醇、矽酸、或其組合。在一些實施例中，以調配物之〜重量计，黏合劑及填充劑佔約1重量°/❶至約25%或約21.5 置％。在一些實施例中，黏合劑係一或多種等級之 MCC，包含（但不限於）Avicel pH 1〇1〜及Avicei ρΗ 1〇2ΤΜ。夺適且朋解劑納入本發明SKI-606調配物中可促進溶 H9415.doc -21· 201113050 解。適宜崩解劑在業内已眾所周知且包含（但不限於）壤月曰碳酸約、馬鈴薯或木著殿粉、藻酸、某些石夕酸鹽、破酸納、交聚維嗣（交聯pvp)i甲基殿粉鈉（澱㈣乙酸鈉）、交聯缓曱基纖維素鈉（交聯叛甲纖維素）、預膠化殿粉 (澱粉1500)、微晶澱粉 '水不溶性澱粉羧甲基纖維素約、石夕酸鎮銘（Veegum)或其組合。在一些實施例中，崩解劑係父聚維嗣。在 '一此营絲/fe丨丨tb 山. 二貫她例中，明解劑係交聯羧甲纖維素納。在些實施例中，適宜潤滑劑包含於本發明如_6〇6調配物中。適宜潤滑劑或助流劑包含(例如)硬脂酸鹽、硬脂基富馬酸鈉、及鎂鹽硬脂酸鎖。以組合物重量計，所用潤滑劑之量為0.2-5重量％之一或多種湖滑劑（包含約〇5重量 %)。在一些實施例中，潤滑劑係硬脂酸鎂。添加一或多種防腐劑可尤其用於包含8耵_6〇6之組合物中，且可防止發生分解及/或沉澱。適宜防腐劑已由彼等熟習此項技術者所熟知，且包含任一醫藥上可接受之防腐劑。習用防腐劑包含（但不限於）苯f酸鈉、對羥基苯曱酸丙酯，山梨酸、對羥基苯甲酸丙酯、對羥基苯甲酸甲酯、丁羥甲苯、丙酸酯、山梨酸鉀、茚地那韋（Indinavir)及其組合。在一些實施例中，以調配物之總重量計，所提供之防腐劑佔約0_05重量％至約〇·25重量％或約〇1重量％。所提供之組合物可調配成單位劑型。該等調配物對於熟習此項技術者已眾所周知。在某些實施例中，本發明提供包括錠劑固體劑型之調配物。在其他實施例中，本發明提 I49415.doc •22- 201113050 供用於經口投與之溶液。在一些實施例中，單位劑型含有 50 mg、75 mg、100 mg、125 mg、150 mg、175 mg、200 mg、225 mg、250 mg、275 mg、300 mg、325 mg、350 mg ' 375 mg、400 mg、425 mg、450 mg、475 mg、或 500 mg、525 mg、550 mg、575 mg、600 mg、625 mg、650 mg、675 mg、700 mg、725 mg、750 mg、775 mg、800 mg ' 825 mg、850 mg、875 mg、900 mg、925 mg、950 mg、975 mg、1000 mg、1025 mg、1050 mg、1075 mg、 1100 mg、1125 mg、1150 mg' 1175 mg、1200 mg、1225 mg、1250 mg、1275 mg、1300 mg、1325 mg、1350 mg、 1375 mg、1400 mg、1425 mg、1450 mg、1475 mg、1500 mg之SKI-606。在一些實施例中，單位劑型含有介於5 mg 至500 mg之間且包含5 mg及500 mg、或介於10 mg至450 mg之間且包含10 mg及450 mg之SKI-606。在一些實施例中，單位劑型含有 50 mg、75 mg、100 mg、150 mg、250 mg、3 00 mg、或500 mg之SKI-606。在一些實施例中’單位劑型含有500 mg以上之SKI-606。在一些實施例中，所用SKI-606之有效劑量可端視所用特定化合物、投與方式及所治療病狀之嚴重程度而有所變化。然而，通常而言，在以下情形時可獲得滿意結果：以約0.5 mg/kg體重至約1000 mg/kg體重之曰劑量投與本發明化合物，視需要以每日2至4次之分開劑量給予，或以持續釋放形式投與。總日劑量預計為約1-1000 mg、較佳約 2-500 mg。適用於内部使用之劑型包括約0.5-1000 mg活性 149415.doc -23· 為-- 201113050 化合物與醫荜卜可調替η二之固體或液體载劑的均勻混合物。 ° 量方案以提供最佳治療反應。舉日投盥芒丰八0日士，θ J ^ ° J母所刀"劑量或該劑量可依照治療情形之緊急程度所不按比例減少。？ ^杜汉 _在之一醫些^施例中’自易於製備及投與之角度考慮，ski- 戍液體填樂穿組合物係固體組合物，尤其係鍵劑及硬質填充 =體填充耀囊。在—較佳實施例中’經σ投與ski_6〇6 為治療癌症，组合偽士 ... ’ 、本發月之SKI-606調配物及其他與放射療法相組合。該等其他物質或放射治法可實現協7合物在相同或不同時間給出。該等組合療盘同性並改善功效。舉例而言本發明化合物可 i她、貝組合使用：有絲分裂抑制劑(例如紅豆杉醇或 (例如5蠢坑基化3式劑（例如順銷或環碌酿胺）、抗代謝藥 (例如5-氟尿嘧啶或羥基 A也主、 } ΝΑ嵌入劑（例如阿黴素或博 =二拓撲異構酶抑制劑(例如依託泊州或喜激夸m几血管生成劑(例如血管他丁 (angi〇statin))、及抗雌激素（例如他莫昔芬（tamoxifen)。 =據在美國專利第6,297,258號中針對如屬及其他3· =唾琳化合物所揭示之結果，本發明如.調配物係 j㈣效能之有用抗贅瘤藥’其可用於治療贊瘤、抑制 I瘤之生長、或根除贅瘤。特定而言，本發明化合物可用 =表現咖之資瘤、抑制該等費瘤之生長、或根除彻，例如乳房、腎、膀胱、口腔、喉、食道、胃、 149415.doc •24- 201113050 結腸、卵巢、或肺之彼等贅瘤。此外’本發明化合物可用於治療表現由erbB2 (Her2)致癌基因產生之受體蛋白質之乳房贅瘤、抑制該等贅瘤之生長、或根除該等贅瘤。^ 所獲得之結果，本發明化合物亦用於治療多囊性腎病。、.組合產物及組合投與：在某些實施例中，本發明組合物、及其調配物可單獨投與以治療-或多種如本文所述之病症，或者可與一或多^ 其他活性劑組合投與（同時或依序）以用於治療-或多種如本文所述之病症。因此，本發明組合物、或其調配物可與 -或多種活性劑同時、在其之前、或在其之後投與。在某些實施例中，除肌6()6外，本發明組合物亦包含一或多種非SKI.之其他活性劑。在―些實施例中，本發明調配物包括另一抗癌化合物及SKI-606。存在於本發明組合物中之額外活性劑之量通常不超過在包括該活性劑作為唯一治療劑之組合物中正常投與之量。在本發明某些實施例中，額外活，劑之量為包括該化合物乍為唯療劑之組合物中所存在正常量的約％%至 100%。在某t貞施例中，本發明調配物亦可與習用療法結合及/ 或組合用於胃腸功能障礙以幫助改善便秘及大腸功能障礙舉例而5 ’習用療法包含（但可不限於）腸道之功能刺 +敫糞便軚化劑、瀉藥(例如，二苯基甲烷瀉藥、導瀉藥谷積14,寫藥、鹽類瀉劑等）、體積成形藥劑及滴藥、、澗滑劑、靜脈内水合、及鼻胃減壓。 149415.doc •25· % 201113050 本發明組合物之用途及套組：供之組&物'及其調配物亦適用於治療包含癌症在内之病狀（涉及血管發生、免疫抑制、鐮狀細胞性貧血、血管創傷、及視網膜病變）、治療炎症相關性病症(例如腸激踪症候群）、免疫抑制、慢性炎症。运在其他實施例中，提供本發明組合物、及其調配物在獸醫應用（例如，治療家養動物，例如馬、狗、猶等）中之用途:因此，涵蓋所提供調配物在獸醫應用中之用途，其與彼等上文針對人類個體所述者類似。亦應瞭解’本發明組合物及其調配物可用於組合療法，即，本發明組合物或其調配物可與—種或多種其他期望療法或醫療程序同時、在其之前或在其之後實施。欲在組合方案中使用之特定組合療法（治療劑或程序）應顧及所需治療劑及/或程序之相容性及欲達成之期望治療效應。亦應瞭解’所用療法可對相同病症達成期望效應(例如，調配In certain embodiments, the MCC rating in the EG component is changed from Avicel PH 149415.doc • 18·201113050 101TM to Avicel PH 102 top to facilitate flow of the tablet blend. In certain embodiments, as opposed to the frequent observation that particle size reduction of Αρι generally results in an increase in dissolution rate, it is observed that for SKI 606 formulations, 5 is the same as with formulations having higher D90 API particle sizes. When the method is processed, reducing the API particle size tends to reduce the dissolution of the formulation. Therefore, it has been observed that the lower the API particle size, the slower the dissolution rate, and the faster the Αρι particle size, the faster the dissolution rate, as summarized in Figure 6. In order to maximize the dissolution, one of the existing formulations may use to increase the particle size of a drug such as SKI-606. To slow down the dissolution, the embodiment uses a lower particle size API. In certain embodiments, the concentration of poloxamer in the SKI-6G6 formulation of the invention is not altered to maintain an in vivo effect when administered to a human or animal subject. In some two μ % of the examples, the formulations of the present invention may contain one or more non-speed monuments, f (four) or coatings. The non-rate controlling layer is not important in the formulation of the tenth place. For example, the non-rate controlling layer can be located between at least one phase and an enteric coating or a rate (tetra) structure. Or can the non-rate controlling layer surround or coat the enteric coating or the rate controlling mechanism? The Γ rK ^ layer consists of one or more polymers and other ingredients known in the art, including, but not limited to, plasticizers, pigments/sunscreens, and the like. Useful polymers include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose, teretrial cellulose, ethylcellulose, % vinyl alcohol, and polyethylene glycol. Examples which may be used include, but are not limited to, polyethylene glycol, glycerin, triacetin, ruthenium-ethyl ester, diethyl phthalate, and mineral oil. Useful Pigments/Mask H9415.doc 201113050 Examples of photocontainers include, but are not limited to, water soluble dyes, pigments, and natural products. In certain embodiments, the formulations of the present invention may also comprise at least one enteric coating. Any enteric coated mash can be used in the present invention, including but not limited to solutions or dispersions of methacrylic acid and methacrylic styrene copolymer, cellulose acetate phthalate, phthalic acid Hydroxypropyl decyl cellulose, hydroxypropyl methylcellulose acetate, phthalate polyvinyl acetate, ethyl acrylate/methacrylic acid copolymer, cellulose acetate trimellitate, insect Glue and its combination. Further, the enteric coating used in the formulation of the present invention may be formed in a single layer or in multiple layers. The thickness of the coating can be readily determined by those skilled in the art, but must be sufficient to protect the formulation in an acidic gastric environment. In certain embodiments, 'based on the use of croscarmellose sodium in place of a conventional disintegrant crospovidone', a pharmaceutically acceptable solid composition of SKI-606 has been invented which can unexpectedly improve SKI-606 The stability of the formulation was obtained and a uniform dissolution rate was obtained (see Table 1 and Figure _3). Wetting agents are well known in the art and generally promote drug release and absorption. Exemplary wetting agents include poloxamers, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyglycol fatty acid S, polyoxyethylene hydrogenated castor oil, polyoxygen Ethyl hydrazine, polysorbate, cetyl alcohol, glycerol fatty acid esters (eg, triacetin, glyceryl monostearate, and the like), polyoxymethylene stearate, sodium lauryl sulfate, Sorbitan fatty acid esters, sucrose fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and Doku vinegar 149415.doc • 20-201113050 Sodium, and the like, and combinations thereof. In some embodiments, the wetting agent includes, but is not limited to, for example, polysorbate 8〇TM, glycerin, polysorbate 65TM, polysorbate 60TM USP, polysorbate 40TM USP , Polysorbate 20TM USP, octylphenol, nonylphenol_1〇~usp, poloxamer 235TM, poloxamer 188TM usp. In some embodiments, the wetting agent is provided in an amount of from about 1% by weight to about 5% by weight, based on the total weight of the formulation, of about 1.0% by weight. /〇 to about 4% by weight, or about 3% by weight. In certain embodiments, the wetting agent is a poloxamer comprising, but not limited to, for example, Poloxamer 188TM (Lutrol F-68). Suitable binders (also known as "diluents" and/or "fillers") are known in the art. For example, δ 'suitable binders and fillers include, but are not limited to, precipitation, dextrin, sucrose, sorbitol, sodium saccharin, potassium acetal sulfonate, xylitol, aspartame 'mannitol, starch, Ρνρ (polyvinylpyrrolidone) is low in HPC (hydroxypropyl cellulose), microcrystalline cellulose (MCC), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxymethyl cellulose, Ethylcellulose, alginate, gelatin, polyoxyethylene' gum arabic, dextrin, sucrose, magnesium aluminum silicate, and polydecyl acrylate. Filler 匕3 is selected from the group consisting of microcrystalline cellulose, starch, lacutol, lactose, a suitable inorganic calcium salt, sucrose, glucose, decyl alcohol, citric acid, or combinations thereof. In some embodiments, the binder and filler comprise from about 1 weight percent to about 25% or about 21.5 percent by weight of the formulation. In some embodiments, the binder is one or more grades of MCC, including but not limited to Avicel pH 1〇1~ and Avicei ρΗ 1〇2ΤΜ. Incorporating and disintegrating agents into the SKI-606 formulation of the present invention can promote the solution of H9415.doc -21·201113050. Suitable disintegrants are well known in the art and include, but are not limited to, lyophilized hydrazine, potato or hibiscus powder, alginic acid, certain oxalates, sodium chlorate, cross-linked vitamins (cross-linking) Pvp)i methyl temple powder sodium (sodium (tetra) sodium acetate), cross-linked slow-sodium cellulose sodium (cross-linked celluloid), pre-gelatinized temple powder (starch 1500), microcrystalline starch 'water-insoluble starch carboxylate Methylcellulose about, Veegum or a combination thereof. In some embodiments, the disintegrant is a parent vesicle. In the case of 'One of the camps/fe丨丨tb mountain.' In her case, the clearing agent is croscarmellin. In some embodiments, suitable lubricants are included in the formulations of the invention, such as -6 〇6. Suitable lubricants or glidants include, for example, stearates, sodium stearyl fumarate, and magnesium stearate locks. The amount of lubricant used is from 0.2 to 5% by weight, based on the weight of the composition, of one or more lake slip agents (containing about 5% by weight). In some embodiments, the lubricant is magnesium stearate. The addition of one or more preservatives can be especially useful in compositions comprising 8 耵 6 6 6 and can prevent decomposition and/or precipitation from occurring. Suitable preservatives are well known to those skilled in the art and include any pharmaceutically acceptable preservative. Conventional preservatives include, but are not limited to, sodium benzene f, propyl p-hydroxybenzoate, sorbic acid, propyl paraben, methyl paraben, butylated hydroxytoluene, propionate, potassium sorbate , Indinavir and combinations thereof. In some embodiments, the preservative is provided in an amount from about 0. 05% by weight to about 〇 25% by weight or about 重量 1% by weight, based on the total weight of the formulation. The compositions provided can be formulated in unit dosage form. Such formulations are well known to those skilled in the art. In certain embodiments, the invention provides formulations comprising a solid dosage form of a tablet. In other embodiments, the invention provides I49415.doc • 22-201113050 for use in a solution for oral administration. In some embodiments, the unit dosage form contains 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg '375 mg , 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg ' 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1025 mg, 1050 mg, 1075 mg, 1100 mg, 1125 mg, 1150 mg' 1175 mg, 1200 mg , 1225 mg, 1250 mg, 1275 mg, 1300 mg, 1325 mg, 1350 mg, 1375 mg, 1400 mg, 1425 mg, 1450 mg, 1475 mg, 1500 mg of SKI-606. In some embodiments, the unit dosage form contains between 5 mg and 500 mg and comprises between 5 mg and 500 mg, or between 10 mg and 450 mg and comprising 10 mg and 450 mg of SKI-606. In some embodiments, the unit dosage form contains 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, or 500 mg of SKI-606. In some embodiments, the unit dosage form contains more than 500 mg of SKI-606. In some embodiments, the effective dose of SKI-606 used may vary depending on the particular compound employed, the mode of administration, and the severity of the condition being treated. In general, however, satisfactory results are obtained in the following situations: administration of a compound of the invention at a dose of from about 0.5 mg/kg body weight to about 1000 mg/kg body weight, optionally divided into two to four times daily. Give, or be administered in a sustained release form. The total daily dose is expected to be from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use include about 0.5-1000 mg of activity 149415.doc -23· is -- 201113050 Compound and medicinal preparations A homogeneous mixture of solid or liquid carriers of η. The regimen provides the optimal therapeutic response. The daily dose of Mangfeng is 80, θ J ^ ° J mother knife " dose or dose can be reduced according to the urgency of the treatment situation. ? ^杜汉_ In one of the doctors' examples, 'from the perspective of ease of preparation and administration, ski- 戍 liquid fill-through composition is a solid composition, especially a key agent and hard filling = body filling sac . In the preferred embodiment, σ is administered with ski_6〇6 for the treatment of cancer, a combination of pseudo-sex, a SKI-606 formulation of this month, and others in combination with radiation therapy. These other substances or radiotherapy can be achieved at the same or different times. These combined therapies are same-sex and improve efficacy. For example, the compounds of the present invention can be used in combination with her: mitotic inhibitors (such as taxol or (for example, 5 stupid 3 formula (such as cisplatin or cyclamin), antimetabolite (such as 5) - Fluorouracil or hydroxy A is also a major, } ΝΑ intercalating agent (such as doxorubicin or Bo = two topoisomerase inhibitors (such as etoposide or a few angiogenic agents (such as angiostatin) )) and anti-estrogen (e.g., tamoxifen). = The results of the invention as disclosed in U.S. Patent No. 6,297,258, to the genus and other s. A useful anti-tumor drug for efficacy. It can be used to treat tumors, inhibit the growth of I tumors, or eradicate tumors. In particular, the compounds of the present invention can be used to express the growth of tumors, inhibit the growth of such tumors, or Radical eradication, such as breast, kidney, bladder, mouth, throat, esophagus, stomach, 149415.doc •24- 201113050 Colon, ovary, or lungs of the tumor. In addition 'the compounds of the invention can be used to treat performance by erbB2 (Her2 Receptor protein produced by oncogene Breast tumors, inhibiting the growth of such tumors, or eradicating these tumors. ^ The results obtained, the compounds of the invention are also used to treat polycystic kidney disease., combination products and combination administration: in some implementations In one embodiment, the compositions of the invention, and formulations thereof, can be administered alone to treat a disease or a plurality of conditions as described herein, or can be administered in combination (simultaneously or sequentially) with one or more other active agents. Treated - or a plurality of conditions as described herein. Accordingly, the compositions of the invention, or formulations thereof, can be administered simultaneously with, before, or after the active agent or agents. In certain embodiments, In addition to muscle 6 (6), the compositions of the present invention also comprise one or more other active agents other than SKI. In some embodiments, the formulations of the present invention comprise another anti-cancer compound and SKI-606. The amount of additional active agent in the composition will generally not exceed the amount normally administered in a composition comprising the active agent as the sole therapeutic agent. In certain embodiments of the invention, the amount of additional active agent is included in the compound.乍 is the composition of the therapeutic agent In some embodiments, the formulation of the present invention may also be combined with conventional therapies and/or used in combination with gastrointestinal dysfunction to help improve constipation and large bowel dysfunction. Therapeutic therapies include (but are not limited to) functional acne in the intestines + sputum sputum sputum sputum, laxatives (eg, diphenylmethane laxatives, cathartic drugs, Guji 14, writing drugs, salt laxatives, etc.), volume forming agents and Drip, sputum, intravenous hydration, and nasogastric decompression. 149415.doc •25· % 201113050 Uses and kits of the compositions of the present invention: The group & 'and its formulations are also suitable for Treatment of conditions including cancer (involving angiogenesis, immunosuppression, sickle cell anemia, vascular trauma, and retinopathy), treatment of inflammation-related disorders (eg, intestinal tract syndrome), immunosuppression, chronic inflammation. In other embodiments, the use of the compositions of the invention, and formulations thereof, in veterinary applications (eg, treatment of domestic animals, such as horses, dogs, quails, etc.) is provided: thus, the provided formulations are included in veterinary applications The uses are similar to those described above for human individuals. It will also be appreciated that the compositions of the present invention and formulations thereof may be used in combination therapy, i.e., the compositions of the present invention or formulations thereof may be administered simultaneously with, prior to, or subsequent to one or more other desired therapies or procedures. The particular combination therapy (therapeutic agent or procedure) to be used in the combination regimen should take into account the compatibility of the desired therapeutic agent and/or procedure and the desired therapeutic effect to be achieved. It should also be understood that the treatment used may achieve the desired effect on the same condition (eg, deployment)

物可與用於治療相同疝、片夕又 yL A 』病症之另—化合物同時投與），或盆可^成不同效應（例如，控制任何副作用）。本文所用通常 =以治療或預防具體疾病或病狀m療化合物稱作適於所治療疾病或病狀」。在其他實施例中，本發明組合 .,, 及具調配物、及單位劑型用於製備藥劑，包含（但不劑。吸於）用於治療癌症之藥本發明進一步涵蓋醫藥包及/或合物、及其調配物、及容器( 。括本發明組今益（例如’箱或塑膠包裳、或其 149415.doc -26· 201113050 他適宜容器）》視需要，在該等套組中另外提供使用說明。為可更全面地理解本文所述之本發明，闡述以下實例。應理解，該等實例僅出於闡釋目的，而不應視為以任何方式限制本發明》本發明各態樣之所有特徵皆適用於所有其他態樣（加以必要之變通）。實例1及2 : SK1-606之醫藥上可接受之組合物之製備根據美國專利第6,297,258號及第7,297,795號中之一或多者中所詳述之方法來製備SKI-606。本發明之實例性SKI-606調配物及對比性SKI-606調配物匯總於表 1 中。表1. SKI-606調配物粒内組份 SKI-606調配物1 對比性SKI-606調配物 (% w/w) (% w/w) SKI-606單水合物（等效於SKI-606游離鹼） 69 69 微晶纖維素(MCC，Avicel PH 101 ™) 6.5 17.5 交聚維酮(CPV) ΝΑ 3 交聯羧曱纖維素鈉(CCS) 2 ΝΑ 泊洛沙姆 188™ (Lutrol F-68) 3 3 聚維酮(Kollidon25™) 2 2 粒内組份之重量％ 82.5 94.5 粒外組份微晶纖維素(MCC, Avicel 101™) ΝΑ 4 微晶纖維素(MCC，Avicel 102™) 15 ΝΑ 交聚維酮 ΝΑ 1 交聯羧曱纖維素鈉 2 ΝΑ 硬脂酸鎂 0.5 0.5 粒外組份之重量°/〇 17.5 5.5 塗層(Opadry II系統） 3 4 NA-不適用或不可用 149415.doc -27- 201113050 使用適宜工藝設備來壓製500 mg強度之錠劑’且在低 (11-13 kp)硬度、目標（14-16 kp)硬度及高（17-19 kp)硬度下壓製錠劑。然後在0.1 N HC1中評價該等錠劑之崩解時間。藉由以下過程來製備對比性SKI-606調配物：尚剪切濕法造粒，濕研磨，流化床乾燥，乾研磨’摻和並壓製成錠劑，隨後塗覆膜。此調配物在空腹個體中與高百分比之胃刺激有關。比較使用習用崩解劑交聚維酮及使用交聯羧曱纖維素鈉之SKI-606調配物的崩解時間且匯總於表2中。此情形中之粒内崩解劑保持恒定於3 % w/w。兩種調配物具有顯著不同之崩解時間，例如，2%粒外（EG) CCS調配物之錠劑崩解時間（DT)僅為3.5分鐘，與之相比’ CPV調配物之DT為22 分鐘。此外’亦觀察到，對於所有CPV調配物而言’錠劑 DT皆高度取決於錠劑硬度’而在CC S調配物中未觀察到該依賴性。舉例而言，即使對於2%之CPV調配物，低硬度錠劑與高硬度錠劑之DT時間相差14分鐘，而CCS調配物僅相差3.5分鐘。此觀察結果表明，CCS調配物在錠劑硬度方面較為穩定。此係錠劑可製造性方面之顯著改善’特定而言，此乃因該等錠劑意欲成為即刻釋放之錠劑。表2.使用交聚維酮及交聯羧甲纖維素鈉作為崩解劑之SKI-606 500 mg劑量調配物的崩解時間。（調配物可參照表2A) 1°/。黏合劑，£0 0?丫-1°/。 1°/。黏合劑，EG CPV-5% 2%黏合劑，EG CPV-2% 試驗1 試驗2 試驗3 低目標硬低目標硬低目標硬 9分56秒 18分20秒 27分20秒 6分37秒 10分45秒 12分 15分25秒 22分10秒 29分20秒 149415.doc -28 - 201113050 2%黏合劑，EG 2%黏合劑， 2%黏合劑，EG 2%黏合劑，EG CPV-5% EG CCS-1% CCS-2 % CPV-1% 試驗4 試驗5 試驗6 試驗7 低目標硬低目標硬低目標硬低目標硬 10分 13分 18分 2分 4分 5分 2分 3分 6分 16分 30分 40分 11秒 30秒 41秒 20秒 10秒 25秒 30秒 35秒 20秒其中，硬質錠劑->16 kp錠劑硬度，目標錠劑-14-16 kp且低硬度-11-13 kp(kp-千帕）表2A :表2中所提及調配物之組成百分比試驗1 試驗2 試驗3 試驗4 試驗5 試驗6 試驗7 粒内部分 SKI-606單水合物，等效於無水驗 69 69 69 69 69 69 69 微晶纖維素(Avicel 101™) 6.5 6.5 5.5 5.5 5.5 5.5 5.5 交聚維酮(CPV) 3 3 3 3 NA NA 3 交聯羧曱纖維素鈉(CCS) NA NA NA NA 3 3 NA 泊洛沙姆 188 (Lutrol F-68™) 3 3 3 3 3 3 3 聚維酮(Kollidon 25™) 1 1 2 2 2 2 2 粒内總量(％) 82.5 82.5 82.5 82.5 82.5 82.5 82.5 粒外部分微晶纖維素(Avicel 101™)** 16 12 15 12 16 15 16 交聚維酮(CPV) 1 5 2 5 NA NA 1 交聯羧曱纖維素鈉(CCS) NA NA NA NA 1 2 NA 硬脂酸鎂 0.5 0.5 0.5 0.5 0.5 0.5 0.5 粒外總量(％) 17.5 17.5 17.5 17.5 17.5 17.5 17.5 亦在0.1 N HC1中溶解本發明SKI-606調配物之錠劑（參見圖1)，其顯示在CCS濃度低於所用CPV濃度下，CCS調配物之錠劑在10及15分鐘時之溶解較快。此外，數據亦顯示，較低黏合劑濃度可尤其在較早時間點時增強溶解作 149415.doc -29- 201113050 用。該等試驗表明，CCS調配物在可處理性方面較佳，與 CPV調配物（其中造粒終點極對水輸入極為敏感）不同，其造粒終點不會突然達到，且CCS調配物之崩解時間（DT)不易受錠劑硬度影響。減少黏合劑可與CPV之適當溶解作用有關。對於包含交聯羧曱纖維素鈉作為崩解劑之本發明SKI-606調配物而言亦顯而易見，溶解作用在 15 分鐘時不易受 API粒徑影響，如表3中所匯總。此外，對於所研究之所有 IG/EG範圍而言，可在15分鐘時較緩慢溶解CCS調配物之唯一比率為1%/0%粒内/粒外崩解劑。對於所有其他含量而言，釋放度皆大於90%。表3 :崩解劑及API D90對500 mg核心錠劑之崩解及溶解的影響崩解劑類型 CPV CPV CPV CCS CCS CCS CCS CCS APID9〇(微米） 38 20 20 20 20 38 38 38 黏合劑(％ w/w) 2 2 1 2 2 2 2 2 IG崩解劑(％ w/w) 3 3 3 3 3 2 1 1 EG崩解劑(％ w/w) 3 3 1 1 0 0 1 0 崩解時間(min) [對於14-16 kp錠劑而言] 18.32 15.73 25.48 4.18 4.75 14.3 7.4 23.4 在15分鐘時於0.1 N HC1中釋放之百分比 67.68 50.21 23.41 94.21 92 97 97.2 67.6 在30分鐘時於0.1 N HC1中釋放之百分比 94 89 47 98 97 101 99 96 該等研究表明，交聯羧甲纖維素鈉調配物在可製造性方面較為優異，其中易於確定造粒終點（可降低過度造粒之 149415.doc -30- 201113050 風險）；交聯羧甲纖維素鈉調配物之崩解時間受錠劑硬度影響較小；且預計降低黏合劑（聚維酮）濃度可增加CPV調配物之溶解速率，此乃因此可影響錠劑崩解速率。可以認為，無需改變展示優異鍵劑崩解時間及溶解作用之ccs調配物之黏合劑濃度，不論黏合劑濃度多大。大量實驗結果表明，交聯羧甲纖維素鈉調配物在藥物物質粒徑中之可變性及穩定狀態下產物溶解曲線之一致性方面更為穩定。藉由以下方式可看到一些優點：改變微晶纖維素之粒内與粒外比率以改善錠劑崩解時間以及摻合物流動性，且保持泊洛沙姆及黏合劑之量與參照組合物中相同。對於包含交聯羧甲纖維素鈉作為崩解劑之本發明SKI_ 606調配物亦顯而易見，粒徑愈小則溶解愈慢，如表2及3 中所匯總。此外，使用任一崩解劑在40°C下（乾法及濕法）於第2週及第4週時’未觀察到不相容性或分解作用。在4〇。匸及 40°C /75% RH條件下進行穩定性研究之批料顯示，在使用 cpv之調配物中觀察到溶解移位，但使用ccs者未發現此情形，如圖2及3中所匯總。根據所量測之數據及結果，發現交聯羧甲纖維素調配物提供優良之SKI-606錠劑調配物，此乃因Apj可變性在穩定狀態下對溶解作用及溶解移位之影響皆得以解決，而使得調配物之變化最小（由此決定黏合劑聚維酮及泊洛沙姆分別保持恆定於2%及3%)。崩解劑類型及IG/EG崩解劑比率 149415.doc 201113050 在臨床中自3:1變為2:2 (% w/w)。圖4及5闡述分別改變交聯羧甲纖維素及交聚維酮之粒内及粒外崩解劑比率對溶解性的影響。實例3 : SKI-606之快速溶解性醫藥上可接受之組合物的製備根據美國專利第6,297,258號及第7,297,795號中之一或多者中所詳述之方法來製備SKI-606。本發明之實例性快速溶解性SKI-606調配物及對比性SKI-606調配物匯總於表4 中。表4.具有交聯羧甲纖維素鈉之實例性快速溶解性SKI-606 調配物。粒内快速溶解性SKI-606調配彳物對比性SKI-606調配物 (% w/w) (% w/w) SKI-606單水合物(等效於無水SKI-606 游離鹼） 69 69 微晶纖維素(101™) 6.5 17.5 交聚維酮(CPV) ΝΑ 3 交聯羧曱纖維素鈉(CCS) 2 ΝΑ 泊洛沙姆 188 (Lutrol F-68™) 3 3 聚維酮(Kollidon 25™) 2 2 粒内部分％ 82.5 94.5 粒外微晶纖維素(10FM) — 4 微晶纖維素(102TM) 15 — 交聚維酮 ΝΑ 1 交聯羧曱纖維素鈉 2 ΝΑ 硬脂酸鎂 0.5 0.5 粒外部分％ 17.5 5.5 m 3 4 NA-不適用或不可用 H9415.doc -32- 201113050 調配物之胃刺激效應可能係由其在胃及上艰甲之滯留時間有所延長引起。本發明SKI_606調配物亦提供藥物更快地溶於GI道中的相對快速溶解性鹽。藥物之快速溶解性鹽包含擰檬酸鹽、琥珀酸酯、富馬酸鹽、Di_Hci、磺酸鹽、乙酸酯、馬來酸鹽、酒石酸鹽、及Hci鹽（舉幾個來說），從而提供用於較快在GI道内溶解或崩解以使藥物快速溶解之SKI-606調配物。較快崩解調配物係藉由對當前調配物作出一些改變來製得。此可藉由在調配物中納入下列改變來達成：使用交聯羧甲纖維素鈉代替崩解劑交聚維酮。與使用交聚維酮時藉由「虹吸」作用促進崩解相比，此崩解劑之作用方式為藉由「膨脹」作用促進在早期發生崩解。發現在與交聚維酉同相當之濃度下可產生較快之崩解作用。除代替崩解劑外，可作出之其他改變係改變微晶纖維素之比率。在粒内減少微晶纖維素Avicel PH 101且在粒外增加以幫助改善崩解劑效能。亦將其等級自Avicel 101變為粒徑較大之Avicel 以改善摻合物流動性及可壓製性。發現此方式可得到較快崩解及溶解之錠劑，預計其二者改善在胃中之胃結果。本發明SKI-606調配物係基於此方式。實例4:呈經塗覆錠劑形式之SKI-606之醫藥上可接受組合物的製備根據美國專利第6,297,258號及第7,297,795號中之一或多者中所詳述之方法來製備SKI-606。本發明SKI-606調配物在兩種不同單位劑量下之實例性經塗覆錠劑匯總於表5 149415.doc -33- 201113050 中。表5.SKI-606調配物在不同單位劑量強度下之經塗覆錠南丨The substance may be administered concurrently with the other compound used to treat the same sputum, the yL A y condition, or the pot may have a different effect (e.g., to control any side effects). As used herein, generally, the compound is treated to treat or prevent a particular disease or condition, and is referred to as being suitable for the disease or condition being treated. In other embodiments, combinations, compositions, and dosage forms of the invention are used in the preparation of a medicament, including (but not in a dose of) a medicament for the treatment of cancer. The present invention further encompasses pharmaceutical packs and/or combinations. And its formulations, and containers (including the present invention group (eg, 'box or plastic bag, or its 149415.doc -26· 201113050, his suitable container), as needed, in the set The following examples are provided to provide a more complete understanding of the invention as described herein. It is understood that the examples are for illustrative purposes only and should not be construed as limiting the invention in any way. All of the features are applicable to all other aspects (with the necessary modifications). Examples 1 and 2: Preparation of a pharmaceutically acceptable composition of SK1-606 according to one or more of U.S. Patent Nos. 6,297,258 and 7,297,795 The method detailed in the preparation of SKI-606. The exemplary SKI-606 formulation of the present invention and the comparative SKI-606 formulation are summarized in Table 1. Table 1. SKI-606 formulation intragranular component SKI -606 Formulation 1 Contrast S KI-606 Formulation (% w/w) (% w/w) SKI-606 monohydrate (equivalent to SKI-606 free base) 69 69 Microcrystalline cellulose (MCC, Avicel PH 101 TM) 6.5 17.5 Povidone (CPV) ΝΑ 3 croscarmellose sodium (CCS) 2 泊 Poloxamer 188TM (Lutrol F-68) 3 3 Povidone (Kollidon25TM) 2 2 % by weight of intragranular component 82.5 94.5 Extragranular component microcrystalline cellulose (MCC, Avicel 101TM) ΝΑ 4 microcrystalline cellulose (MCC, Avicel 102TM) 15 交 crospovidone 1 croscarmellose sodium 2 硬 stearic acid Magnesium 0.5 0.5 Weight of the outer component °/〇17.5 5.5 Coating (Opadry II system) 3 4 NA-Not applicable or not available 149415.doc -27- 201113050 Use suitable process equipment to suppress 500 mg strength tablets The tablets were pressed at low (11-13 kp) hardness, target (14-16 kp) hardness and high (17-19 kp) hardness. The disintegration time of the tablets was then evaluated in 0.1 N HCl. Comparative SKI-606 formulations were prepared by the following procedure: wet shear granulation, wet milling, fluid bed drying, dry milling 'doping and pressing into tablets, followed by coating. It was associated with a high percentage of gastric irritation in fasting individuals. The disintegration time compared using conventional crospovidone disintegrating agents and the use of cross-linked sodium carboxymethyl cellulose Yue SKI-606 formulation and is summarized in Table 2 below. In this case, the intragranular disintegrant remained constant at 3 % w/w. The two formulations have significantly different disintegration times, for example, a 2% extragranular (EG) CCS formulation has a tablet disintegration time (DT) of only 3.5 minutes compared to a 'CPV formulation with a DT of 22 minute. Furthermore, it has also been observed that for all CPV formulations, the tablet DT is highly dependent on the tablet hardness' and this dependence is not observed in the CCS formulation. For example, even for a 2% CPV formulation, the DT time of the low hardness tablet and the high hardness tablet differed by 14 minutes, while the CCS formulation only differed by 3.5 minutes. This observation indicates that the CCS formulation is relatively stable in terms of tablet hardness. A significant improvement in manufacturability of the tablet is made to the extent that it is intended to be an immediate release tablet. Table 2. Disintegration time of SKI-606 500 mg dose formulation using crospovidone and croscarmellose sodium as disintegrant. (Refer to Table 2A for the formulation) 1 ° /. Adhesive, £0 0?丫-1°/. 1°/. Adhesive, EG CPV-5% 2% binder, EG CPV-2% Test 1 Test 2 Test 3 Low target hard low target Hard low target Hard 9 minutes 56 seconds 18 minutes 20 seconds 27 minutes 20 seconds 6 minutes 37 seconds 10 45 seconds 12 minutes 15 minutes 25 seconds 22 minutes 10 seconds 29 minutes 20 seconds 149415.doc -28 - 201113050 2% binder, EG 2% binder, 2% binder, EG 2% binder, EG CPV-5 % EG CCS-1% CCS-2 % CPV-1% Test 4 Test 5 Test 6 Test 7 Low target Hard low target Hard low target Hard low target Hard 10 points 13 points 18 points 2 points 4 points 5 points 2 points 3 points 6 minutes, 16 minutes, 30 minutes, 40 minutes, 11 seconds, 30 seconds, 41 seconds, 20 seconds, 10 seconds, 25 seconds, 30 seconds, 35 seconds, 20 seconds. Among them, hard tablets->16 kp tablet hardness, target tablet -14-16 kp and low Hardness -11-13 kp (kp-kPa) Table 2A: Percent composition of the formulations mentioned in Table 2 Test 1 Test 2 Test 3 Test 4 Test 5 Test 6 Test 7 Partial SKI-606 monohydrate, Equivalent to no water test 69 69 69 69 69 69 69 Microcrystalline cellulose (Avicel 101TM) 6.5 6.5 5.5 5.5 5.5 5.5 5.5 crospovidone (CPV) 3 3 3 3 NA NA 3 croscarmellose sodium ( CCS) NA NA NA NA 3 3 NA Polo Lumrol 188 (Lutrol F-68TM) 3 3 3 3 3 3 3 Povidone (Kollidon 25TM) 1 1 2 2 2 2 2 Total amount in the grain (%) 82.5 82.5 82.5 82.5 82.5 82.5 82.5 Extra-partial micro Crystalline cellulose (Avicel 101TM)** 16 12 15 12 16 15 16 crospovidone (CPV) 1 5 2 5 NA NA 1 croscarmellose sodium (CCS) NA NA NA NA 1 2 NA stearic acid Magnesium sulphate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Extra-grain total (%) 17.5 17.5 17.5 17.5 17.5 17.5 17.5 Lozenges of the SKI-606 formulation of the invention are also dissolved in 0.1 N HCl (see Figure 1), which is shown in CCS At concentrations below the CPV concentration used, the tablets of the CCS formulation dissolve faster at 10 and 15 minutes. In addition, the data also shows that lower binder concentrations can be enhanced especially at earlier time points 149415.doc -29- 201113050. These tests have shown that CCS formulations are better in treatability, unlike CPV formulations (where the granulation endpoint is extremely sensitive to water input), the granulation endpoint is not abruptly reached, and the collapse of the CCS formulation Time (DT) is not easily affected by the hardness of the tablet. Reducing the binder can be related to the proper dissolution of the CPV. It is also apparent that the SKI-606 formulation of the present invention comprising croscarmellose sodium as a disintegrant is not susceptible to API particle size at 15 minutes, as summarized in Table 3. In addition, the only ratio of the slower dissolution of the CCS formulation at 15 minutes was 1%/0% intragranular/extragranular disintegrant for all IG/EG ranges studied. For all other levels, the release is greater than 90%. Table 3: Effect of disintegrant and API D90 on disintegration and dissolution of 500 mg core lozenge Disintegrant type CPV CPV CPV CCS CCS CCS CCS CCS APID9〇 (micron) 38 20 20 20 20 38 38 38 Adhesive ( % w/w) 2 2 1 2 2 2 2 2 IG disintegrant (% w/w) 3 3 3 3 3 2 1 1 EG disintegrant (% w/w) 3 3 1 1 0 0 1 0 Solution time (min) [for 14-16 kp tablets] 18.32 15.73 25.48 4.18 4.75 14.3 7.4 23.4 Percentage of release in 0.1 N HC1 at 15 minutes 67.68 50.21 23.41 94.21 92 97 97.2 67.6 at 30 minutes at 0.1 Percentage of release in N HC1 94 89 47 98 97 101 99 96 These studies show that the croscarmellose sodium formulation is superior in manufacturability, and it is easy to determine the granulation end point (the 149415 can reduce excessive granulation) .doc -30- 201113050 risk); the disintegration time of the croscarmellose sodium formulation is less affected by the hardness of the tablet; and it is expected that reducing the concentration of the binder (povidone) increases the dissolution rate of the CPV formulation. This can therefore affect the disintegration rate of the tablet. It is believed that there is no need to change the binder concentration of the ccs formulation exhibiting excellent bond disintegration time and dissolution, regardless of the binder concentration. A large number of experimental results show that the variability of the croscarmellose sodium formulation in the particle size of the drug substance and the consistency of the product dissolution curve in the steady state are more stable. Some advantages can be seen by changing the intragranular to extragranular ratio of microcrystalline cellulose to improve tablet disintegration time and blend flow, and to maintain the amount of poloxamer and binder combined with the reference. The same thing. It is also apparent that the SKI_606 formulation of the present invention comprising croscarmellose sodium as a disintegrant has a slower dissolution as the particle size is as summarized in Tables 2 and 3. Further, incompatibility or decomposition was not observed at any of the disintegrating agents at 40 ° C (dry and wet) at the 2nd week and the 4th week. At 4 〇. The batches subjected to stability studies at 40 ° C / 75% RH showed that dissolution shift was observed in the formulation using cpv, but this was not observed with ccs, as summarized in Figures 2 and 3. . Based on the measured data and results, it was found that the croscarmellose formulation provided an excellent SKI-606 tablet formulation, which was due to the effect of Apj variability on the dissolution and dissolution shift under steady state conditions. The solution was made to minimize the change in the formulation (thus determining that the binder povidone and poloxamer remained constant at 2% and 3%, respectively). Disintegrant type and IG/EG disintegrant ratio 149415.doc 201113050 In the clinical change from 3:1 to 2:2 (% w/w). Figures 4 and 5 illustrate the effect of varying the ratio of intragranular and extragranular disintegrant ratios of croscarmellose and crospovidone to solubility, respectively. Example 3: Rapid Solubility of SKI-606 Preparation of a Pharmaceutically Acceptable Composition SKI-606 was prepared according to the method detailed in one or more of U.S. Patent Nos. 6,297,258 and 7,297,795. Exemplary fast soluble SKI-606 formulations and comparative SKI-606 formulations of the present invention are summarized in Table 4. Table 4. Exemplary fast soluble SKI-606 formulations with croscarmellose sodium. Intragranular rapid solubility SKI-606 formulated with sputum Comparative SKI-606 formulation (% w/w) (% w/w) SKI-606 monohydrate (equivalent to anhydrous SKI-606 free base) 69 69 micro Crystalline cellulose (101TM) 6.5 17.5 crospovidone (CPV) ΝΑ 3 croscarmellose sodium (CCS) 2 ΝΑ poloxamer 188 (Lutrol F-68TM) 3 3 povidone (Kollidon 25 TM) 2 2 intragranular fraction % 82.5 94.5 extragranular microcrystalline cellulose (10FM) — 4 microcrystalline cellulose (102TM) 15 — crospovidone 1 crosslinked carboxyindole sodium 2 ΝΑ magnesium stearate 0.5 0.5 Extracellular fraction % 17.5 5.5 m 3 4 NA - Not applicable or not available H9415.doc -32- 201113050 The gastric irritation effect of the formulation may be caused by an increase in the residence time of the stomach and upper armor. The SKI_606 formulation of the present invention also provides a relatively fast soluble salt of the drug which dissolves more rapidly in the GI tract. The fast-dissolving salts of the drug include citrate, succinate, fumarate, Di_Hci, sulfonate, acetate, maleate, tartrate, and Hci (for several). Thereby a SKI-606 formulation for faster dissolution or disintegration in the GI tract for rapid dissolution of the drug is provided. The faster collapse demodulation ligand is made by making some changes to the current formulation. This can be achieved by including the following changes in the formulation: the use of croscarmellose sodium in place of the disintegrant crospovidone. Compared with the use of crospovidone to promote disintegration by the action of "siphon", the disintegrant acts by promoting "disintegration" at an early stage. It was found to produce a faster disintegration at a concentration comparable to that of the merging. In addition to replacing the disintegrant, other changes that can be made change the ratio of microcrystalline cellulose. Microcrystalline cellulose Avicel PH 101 was reduced in the granules and added extragranularly to help improve disintegrant efficacy. It has also changed its grade from Avicel 101 to Avicel with a larger particle size to improve blend flowability and compressibility. It has been found that this method results in a faster disintegrating and dissolving lozenge which is expected to improve gastric outcome in the stomach. The SKI-606 formulation of the present invention is based on this approach. Example 4: Preparation of a pharmaceutically acceptable composition of SKI-606 in the form of a coated tablet. SKI-606 was prepared according to the method detailed in one or more of U.S. Patent Nos. 6,297,258 and 7,297,795. . Exemplary SKI-606 formulations of the present invention are disclosed in Table 5 149415.doc-33-201113050 in two different unit dosages of exemplary coated tablets. Table 5. Coated ingots of SKI-606 formulations at different unit dose strengths

主張：69.0% 批量：25 Kg 成份功能基於旋劑核心基於粒内固體部分輸入/劑量單位 (對於500 mg 刻量強度）輪入/劑量單位 (對於100 mg 劑量強度） —-— 代表性桃料配方 % wt/wt % wt/wt 輸入單位輸入位 —--^ 輪入單位 SKI-606 單水合物，等效於無水驗活性劑 68.96 83.6 500 mg 100.0 mg --- 17.241 微晶纖維素 (PH101” 填充劑 6.50 7.9 47.1 mg 9.420 mg1 ~L62A~ ------ Kg 交聯羧曱纖維素納崩解劑 2.0 2.4 14.49 mg 2.898 mg 0.500 Kg 泊洛沙姆 188 潤濕劑 3.0 3.6 21.74 mg 4.348 mg 0.750 Kg 聚維酮， K-25 黏合劑 2.0 2.4 14.49 mg 2.898 mg 0.500 Kg 純化水b 造粒溶液 QS QS 241.86 mg 48.37 mg 8.340 Kg 總量 82.46 100 597.820 mg 119.564 mg 20.615 Kg 乾燥摻合物及塗層部分：表6.乾燥摻合物及經塗覆SKI-606調配物成份功能基於錠劑核心，％ wt/wt 輸入/劑量單位輸入 (500 mg) 輸入/劑量單位輸入早 (100 mg)位代表性批料配方輪入單位乾燥SKI-606造粒部分 ΝΑ 82.46 597.820 119.564 mg 20.615 Kg 微晶纖維素（PH 102) 填充劑 15.042 109.055 21.811 mg 3.761 Kg 149415.doc -34· 201113050 交聯羧曱纖維素鈉崩解劑 2.0 14.5 2.900 mg 0.500 Kg 硬脂酸鎂潤滑劑 0.5 3.625 0.725 mg 0.125 Kg 總量 100.0 725.00 145.000 mg 25.0 Kg 塗層 Opadry-II yellow, 85F12390 塗覆劑 3.0 NA 4.350 mg 0.975 Kg Opadry-II red, 85F15642 21.75 NA 純化水塗覆載劑 QS 123.25 24.650 mg 5.525 Kg 總量 103.0 746.75 149.350 mg 6.5 Kg 如下所述來製備SKI-606調配物及SKI-606調配物之經塗覆錠劑：製備程序如下所述來製備SKI-606調配物及SKI-606調配物之經塗覆錠劑：以25 Kg之批量稱取下列成份： SKI-606單水合物 17.241 Kg 微晶纖維素（Avicel PH 101) 1.624 Kg 交聯羧甲纖維素鈉0.5 Kg 聚維酮K-25 0.5 Kg 泊洛沙姆0.75 Kg 1.將聚維酮及泊洛沙姆溶於純化水中。 2_向高剪切造粒器中添加粒内部分之SKI-606、微晶纖維素（PH 101)、及交聯羧曱纖維素鈉並最少混合4分 •35- 149415.doc 5- 201113050 釦’或直至均勻。若需要，可在預摻和之前使乾燥成份經過篩以去除團塊。 3. 在的同時，向高剪切造粒器中添加步驟1溶液並混合直至達成適宜顆粒。若需要，可調節水量以達到滿意的造粒終點。 4. 方需要，可在乾燥前使顆粒經過磨機或篩以促進岣勻造粒^ 5. 在流化床乾燥胃巾乾燥顆粒直至達到滿意終點。此時’測試溫度條件下之L〇D應低於3〇/〇 w/w，其中目標為 1 -1.5% w/w。 6_使乾燥顆粒經過配備有適宜濾網或篩之磨機以促進達成用於摻和之滿意粒徑分佈。保留此部分以用於步驟10。 7. 將顆粒添加至適宜摻和器中。若需要，將乾燥之分級顆粒混合最少5分鐘，或直至均勻。 8. 基於乾燥顆粒之所獲得產率，計算粒外成份之量。 9. 可將乾燥摻合物成份經過篩，隨後摻和。若需要，保留微晶纖維素試樣以用於在步驟1〇中進行摻和。向混合器中添加微晶纖維素及交聯羧甲纖維素鈉並摻和10分鐘，或直至均勻。 10. 將來自步驟6之一部分顆粒或來自步驟9之微晶纖維素（PH 102)添加至硬脂酸鎂中並混合以形成潤滑劑預捧合物。將該潤滑劑預摻合物添加至步驟9摻和器中並混合最少2分鐘，或直至均勻。 149415.doc •36· 201113050 11.使用適宜工具在適當硬度下壓製顆粒。塗覆懸浮液之製備及施加 1. 若需要，在混合前，使乾燥顏料經過篩。使用適宜混合器及罐，向顏料塗層中添加純化水並混合直至形成滿意懸浮液。可經由適宜篩來篩分該懸浮液。 2. 將5 Kg塗覆懸浮液施加至床上以總共3% wt/wt重量增益。若需要，此可藉由錠劑重量增益來證實。表7 :具有交聚維酮崩解劑之SKI-606調配物在不同單位劑量下之經塗覆錠劑實例成份鍵劑核心重量之 Qty (% w/w) 100 mg劑量鍵劑之Qty/錠劑 (mg) 500 mg劑量鍵劑之 Qty/敍:劑(mg) SKI 606單水合物 (基於96%分析） 69 104.17 520.83 Avicel pH 101 7.5 6.7 33.52 交聚維酮 1.0 1.45 7.25 泊洛沙姆-188™ 3.0 4.35 21.74 聚維酮 2.0 2.9 14.49 水 QS 粒外成份交聚維酮 3.0 4.35 21.74 Avicel pH 101™ 14.0 20.29 101.45 硬脂酸鎂 0.5 0.724 3.62 未經塗覆鍵劑之總重量（mg) 145.0 725.0 Opadry II Yellow 85F12390 ' 4%w/w 6.04 — Opadry II Red 85F15642 85F12390，4% w/w ~ 30.19 經塗覆錠劑之總錠劑重量（mg) 151.04 755.19 149415.doc -37- 201113050 如下所述來製備批量為1 Kg核心錠劑之SKI-606調配物及SKI-606調配物之經塗覆銳劑：稱取下列成份： SKI-606單水合物 718.4 g 微晶纖維素（Avicel PH 101) 46.23 g 交聚維酮10.0 g 聚維酮Κ·25 20.00 g 泊洛沙姆188 30.00 g 1. 使來自步驟1之SKI-606、微晶纖維素及交聚維酮經過20網目篩且將各成份添加至高剪切混合器中。 2. 在低單速（僅葉輪）下將步驟2中之成份在高剪切造粒器中混合2分鐘。 3. 在另一混合器中將泊洛沙姆ι88及聚維酮尺_25溶於純化水中。使用低混合器速度以避免生成發泡體。 4. 將葉輪及斬波器速度設定於低設定值下。使用幫浦添加來自步驟4之溶液以對步驟3中之混合物實施造粒。若需要’在耗盡造粒溶液時，使用斬波器及葉輪在低速下另外繼續混合2-5分鐘。若需要，添加額外純化水同時混合直至達到造粒終點。檢查期望之造粒終點。若可行’記錄用於造粒之總水量及總混合時間以及功率或扭矩讀數。 5. 將顆粒在流化床乾燥器中乾燥，其中對於丨至 2.5%之建議L.O.D.範圍，入口建議設定值溫度為 149415.doc -38· 201113050 70°C±5°C。稱量並記錄產量。 6·在低速下使乾燥顆粒經過c〇mil(建議磨機速度為彻 rpm或更低且建議筛為2〇網目）。稱量並記錄產"量“、。00 最終摻合：、$。 7.基於步驟7中之產量，計算（粒外）乾燥添加所需之成份量。 8·將來自步驟9之研磨顆粒轉移至適宜尺寸之摻和器中· 〇 9·稱取微晶纖維素（PH 1〇1)、交聚維剩且使其穿過網目筛並添加至步驟n中之V-摻和器中。在無增強桿作用之情形下摻和10分鐘。 1 〇 ·使硬脂酸鎂穿過3 〇 _網目筛且與步驟i 2之相等部分之顆粒進行袋式摻和並添加至¥_摻和器中。在無增強桿之情形下摻和2分鐘。曰 11·稱量並記錄產量。壓製已知重量及硬度之錠劑並將膜塗覆於經壓製錠劑上。在某二貫把例中，本發明SKI_606調配物消除了關於氛基唾琳固體調配物之一或多個問題，該等問題亦即：在緩衝溶液或酸性條件下測試時，某些SKI_606調配物（參見對比性實例）在室溫及加速條件下溶解作用可有所改變且陳化後之/谷解性可能發生較小但顯著之移位，如圖1 〇及i 2 中所匯總。圖11展示交聯羧曱纖維素調配物之溶解性並未發生移位。圖12展示現有調配物之溶解移位。SKI_606對 149415.doc 39· 201113050 比性調配物中之泊》沙姆188係造成所觀察到的溶解移位的原因。泊洛沙姆儘管在室溫下為固體，但其在接近其熔點48-52 C之溫度下及在該溫度周圍往往會發生液化。圖 13及14中匯總之研究顯示，基於交聚維酮之調配物中之泊 /各沙姆係錠劑發生溶解移位的真正原因。在某些實施例中，使用不同量之泊洛沙姆（〇、15% w/w、3% w/w、4 5% w/wA 6% w/w，基於 SKi 6〇6調配物之重量）來製備SKI_6〇6錠劑調配物。意想不到的是，據觀察，在〇· 1 N HC1中測試時，錠劑溶解作用對調配物中泊洛沙姆之含量百分比存在顯著依賴性。圖13匯總了在相似水及黏s劑添加速率下在〇丨N HQ中不同泊洛沙姆含量對錠劑溶解作用之影響。據觀察，尤其在較早時間點，泊洛沙姆只際上可妨礙所測試錠劑之釋放。泊洛沙姆似乎可在15 及30分鐘時以濃度依賴性方式妨礙初始錠劑溶解。參見表表8.具有不同泊洛沙姆含量之SKI-606 500mg旋劑核心在0丨N HC1中之崩解時間泊洛沙姆濃度 DoE-1/試驗編號錠劑之DT範圍丨N=6)(min) 0 -—~~~~~_____ 2 6.2-6.6 1.5 1 10.6-12.9 3.0 3 11.5-13.1 4.5 7 14.1-15.6 6.0 5 14.3-14.9 儘管錠劑中之泊洛沙姆在初始易於阻礙溶解，但發現其在稍後時間點在〇. 1 N HC1介質中使在加速穩定狀態下之溶 1494l5.doc •40· 201113050 解作用加速，如表9中所匯總之數據所看到。表9 : D〇E批料在〇.1NHC丨及pH4緩衝液中之溶解百分比的增加(穩定水 (G) 黏合劑添加速率 (g/min) 泊洛沙姆 (% w/w) 在0.1 N HC1中在15分鐘時之釋放(％> (+與初始時相比溶解％之增加） 147 58.5 0 初始 66 1M，在40°C 下 +3 1M，在40°C/75°/〇RH下 +6 162 58.5 1.5 初始 50 1M，在40°C 下 +19 1M，在40°C/75% RH下 +22 147 58.5 3.0 初始 43 1M，在40°C 下 +11 1M，在40°C/75% RH下 +31 158 66 4.5 初始 38 1M，在40°C 下 +13 1M，在40°C/75% RH下 +8 147 58.5 6.0 初始 38 1M，在40°C 下 +6 1M，在40°C/75% RH下 +14 在加速穩定狀態下，泊洛沙姆導致以濃度依賴方式自 0 % w/w至3 % w/w發生溶解移位。在溶解移位超過3 %時，泊洛沙姆濃度趨於平穩而無明顯趨向。該等結果證實，泊洛沙姆可在穩定狀態下引起溶解移位。據信，發生陳化後及在加速溫度下之泊洛沙姆鏈變得更易移動，且因此代之以在錠劑中使顆粒固持於一起，移動性聚合物鏈往往會 -41 - 149415.doc 201113050 「軟化」鍵劑。此情形可能係、心顆粒隨時㈣化以及崩解趨勢增加。亦發現 *軟減少。-旦錠劑已發生崩解，㈣2態下朋解時間有所朋解貝1錠劑中之顆粒實際上展子與所有已知表面活性劑極相似之 “ > 丁馮增加表面活性劑往彺會增加顆粒溶解作用，如圖14中所看到。本發明S°-606調配物可消除此溶解移位問題，复係藉由代替調配物中亦用作表面活性劑之潤濕劑泊洛沙姆來^ 成。使用溶點較低之表面活性劑（在室溫下係液體者）可幫助解決此問題。聚氧乙稀（20)山梨醇肝單油酸酯（TweenTM 或聚山梨醇醋80,係常用表面活性劑之一。在調配物中所測試聚氧乙烯（20)山梨醇酐單油酸㈣聚氧乙婦山梨醇肝單油酸醋（Tween-80广）之濃度為1%(代替3%之泊洛沙姆）。此可用於具有3% IG及1% EG CPV作為崩解劑之cpv調配物中。我們認為此情形可以接受，此乃因在此漠度下測試之溶解作用及其他可製造性特性可以接受。此外，聚氧乙稀山梨醇酐單油酸酯（Tween_8〇)TM係常用之醫藥上可接受之潤濕劑且亦用作表面活性劑。除解決溶解移位外，期望測試該等調配物在活性醫藥成份API粒徑方面之穩定性。在對比性SKI_6〇6調配物中， API粒徑似乎會影響溶解作用，亦即，Αρι粒徑愈小，溶解愈慢。對於SKI/Tween-80調配物，此效應可降至最低或忽略不計（圖17)且包括替代潤濕劑聚氧乙烯山梨醇酐單油酸酯（Tween-80)™之SKI_606調配物在陳化（圖丨5及16)中優於對比性SKI-606調配物。 149415.doc • 42- 201113050 實例11及12 : SKI-606之醫藥上可接受之組合物的製備根據美國專利第6,297,258號及第7,297,795號中之一或多者中所詳述之方法來製備SKI-606。本發明之實例性SKI-606調配物及對比性SKI-606調配物匯總於表10中。表10. SKI-606調配物粒内組份 SKI-606調配物1 對比性SKI-606調 SKI-606替代表面配物活性劑調配物 (% w/w) (% w/w) (% w/w) SKI-606單水合物，等效於 SKI-606鹼 69 69 69 微晶纖維素(MCC，Avicel PH101) 6.5 17.5 19.5 交聚維酮(CPV) ΝΑ 3 3 交聯羧曱纖維素鈉(CCS) 2 ΝΑ ΝΑ 泊洛沙姆 188™ (Lutrol F-68™™) 3 3 ΝΑ 聚氧乙烯山梨醇酐單油酸酯 (Tween -80) 1 聚維酮(Kollidon 25) 2 2 2 粒内組份之重量％ 82.5 94.5 94.5 粒外成份微晶纖維素(MCC,Avicel 101™) ΝΑ 4 4 微晶纖維素(MCC,Avicel 102™) 15 ΝΑ ΝΑ 交聚維酮 ΝΑ 1 1 交聯羧甲纖維素鈉 2 ΝΑ ΝΑ 硬脂酸鎂 0.5 0.5 0.5 粒外組份之重量％ 17.5 5.5 5.5 塗層(Opadryll系統） 3 4 4 149415.doc •43- 201113050 ΝΑ-不適用或不可用包括聚氧乙烯山梨醇酐單油酸酯（Tween_8〇)作為潤濕劑之替代性SKI-606調配物匯總於表〗1-13中。表11.包括聚乳乙烯山梨醇酐單油酸g旨（Tween-80)及不同交聚維酮濃度之替代性SKI -606調配物 ο 成份替代性Tween 調配物 (% w/w) 替代性Tween 調配物 (% w/w) 替代性Tween 調配物 (% w/w) SKI-606單水合物，等效於SKI-606鹼 69 69 69 微晶纖維素(MCC，Avicel PH101) 21.5 20.5 18.5 交聚維酮(CPV) 1 2 4 交聯羧曱纖維素鈉(CCS) ΝΑ ΝΑ ΝΑ Tween-80™ 1 1 1 聚維酿)(Kollidon 25TM) 2 2 2 粒内組份之重量。/〇 94.5 94.5 94.5 微晶纖維素(MCC，Avicel 101) 2 3 5 交聚維酮 3 2 0 硬脂酸鎂 0.5 0.5 0.5 粒外組份之重量°/〇 5.5 5.5 5.5 149415.doc •44· 201113050 表12·包括不同聚氧乙晞山梨醇gf單油酸g旨（Tween-80)濃度之替代性SKI-606調配物。成份替代性Tween 替代性Tween 替代性Tween 調配物調配物調配物 (% w/w) (% w/w) (% w/w) SKI-606單水合物，等效於SKI-606鹼 69 69 69 微晶纖維素(MCC, Avicel PH 101) 20 20.25 19.75 交聚維酮(CPV) 3 3 3 交聯羧曱纖維素鈉(CCS) ΝΑ ΝΑ ΝΑ Tween-80™ 0.5 0.25 0.75 聚維酮(Kollidon25) 2 2 2 粒内組份之重量％ 94.5 94.5 94.5 微晶纖維素(MCC, Avicel 101) 4 4 4 交聚維酮 1 1 1 硬脂酸鎂 0.5 0.5 0.5 粒外組份之重量％ 5.5 5.5 5.5 149415.doc -45· 201113050 表13.包括聚氧乙烯山梨糖醇酐單油醆酯（Tween_8〇)且具有不同黏合劑濃度之替代性SKI-606調配物。成份 -------- 替代性Tween替代性Tween替代性了^^印調配物調配物調配物 (% W/W) (% w/w) ί〇/„ w/w) SKI-606單水合物，等效於SKI-606鹼 69 69 69 微晶纖維素(MCC，Avicel PH101) 20.5 19.5 18.5 交聚維酮(CPV) 3 3 3 交聯羧曱纖維素鈉(CCS) ΝΑ ΝΑ ΝΑ Tween-80™ 1 1 1 聚維酮(Kollidon25) 1 2 3 粒内組份之重量％ 94.5 94.5 94.5 微晶纖維素(MCC，Avicel 101) 4 4 4 交聚維酮 1 1 1 硬脂酸鎂 0.5 0.5 0.5 粒外組份之重量％ 5.5 5.5 5.5 藉由以下過程來製備對比性SKI-606調配物：高剪切濕法造粒’濕研磨，流化床乾燥，乾研磨，摻和並壓製成錠劑，隨後塗覆膜。在某些實施例中，本發明SKI-606調配物包括藉由高剪切濕法造粒或盤式塗覆製得之塗覆膜的SKI-606調配物。在其他實施例中，塗覆膜之SKI-606錠劑調配物係藉由其他習用塗覆技術製得。【圖式簡單說明】 149415.doc -46- 201113050 圖1匯總了比較不同崩解劑（交聯羧甲纖維素鈉對交聚維酮）之SKI-606調配物之錠劑溶解速率。圖2匯總了包含交聚維酮之SKI-606調配物在加速穩定狀態下之溶解作用。錠劑尤其在較早時間點似乎具有顯著溶解移位。圖3匯總了包含交聯羧曱纖維素鈉之SKI-606調配物在加速穩定狀態下之溶解作用。在此情形中未觀察到移位（與圖2相比）。圖4匯總了 SKI-606調配物中之不同粒内及粒外（IG及EG) 交聯羧甲纖維素鈉濃度對錠劑溶解速率之影響。圖5匯總了 SKI-606調配物中之不同粒内及粒外（IG及EG) 交聚維酮濃度對錠劑溶解速率之影響。此處可觀察到較寬的溶解作用，此表明溶解作用對交聚維酮之比率之強濃度依賴性。含有D90 API之調配物的溶解作用與其他含有 D90 = 40或60微米之API者似乎顯著不同。圖6匯總了活性醫藥成份（API)粒徑對含有交聚維酮且含有2%黏合劑、及2%粒内及粒外崩解劑之SKI-606調配物之溶解作用的影響。圖7A及B匯總了在CTAB/乙酸鹽及0·1 N HC1介質中API 粒徑對基於交聯羧曱纖維素鈉之SKI-606調配物沒有影響。CTAB/乙酸鹽介質被視為辨別性較〇·1 N HC1更強之介質。比較此圖與圖9Α及Β，圖9Α及Β可顯著展示API粒徑對基於交聚維酮之錠劑調配物之錠劑溶解作用的不同影響。圖8匯總了基於交聯羧曱纖維素之SKI-606調配物（試驗 149415.doc • 47· 201113050 A、B及C)對錠劑硬度（在120·190 Ni範圍内）沒有溶解依賴性’由此證明了調配物之溶解穩定性。在製備裝置中，通常可能需要改變錠劑硬度，且此調配物明顯可提供此能力。圖9八及8匯總了 API粒徑對基於交聚維酮之調配物在〇 ι N HC1中之錠劑（100及500 mg強度）溶解作用的影響。比較及對比此圖與不展示此依賴性之圖7a及7B。圖〗〇匯總了 500 mg基於交聚维酮之5耵_6〇6調配物在敞口盤加速穩定狀態下長達2週時之錠劑溶解作用之向上移位《展示具有2種不同黏合劑百分比及崩解劑比率之調配物之溶解數據。在兩批次之錠劑溶解期間，在早期皆可觀察到顯著溶解差異，此表明在加速穩定狀態下沒有溶解重現性。比較及對比此調配物與圖】】令在穩定狀態下並不展不任何差異之基於交聯羧曱纖維素鈉的調配物。〜圖11匯總了基於交聯叛甲纖維素鋼（ccs)之調配物在穩定狀態下在與圖10中交聚維酮（cpv)批料相似之條件下沒有任何溶解移位。圖12展示交聚維鲷（cpv) SKI_6〇6調配物之⑽及！⑻邮強度錠劑在加速陳化條件下於Q1 NHC1中之額外溶解移位數據在0.1 N HC1觀察到兩種強度之錠齊丨皆具有一致之向上趨勢。 " 圖13匯總了具有不同濃度潤濕劑（泊洛沙姆）之SKI.606調配物之對比性溶解曲線。據觀察，泊洛沙姆具有以濃度依賴性方式降低錠劑溶解作用之意想不到的效應。 149415.doc •48· 201113050 圖14匯總了潤濕劑對SKI-606調配物中之顆粒溶解作用的影響。此影響展示，增加泊洛沙姆濃度可使顆粒溶解作用增加。圖15匯總了在40°C及40°C /75% RH之敞口盤條件下加速陳化達6週對含有聚氧乙烯山梨醇酐單油酸酯（Tween-80)作為潤濕劑（API D9G=38微米）之SKI-606調配物的影響。據觀察，即使在敞口盤之苛刻穩定性條件下，移位似乎可忽略不計。圖16匯總了在40°C及40°C/75% RH下加速陳化達6週之開放盤條件對含有聚氧乙烯山梨醇酐單油酸酯（Tween-80)作為潤濕劑（API D9〇= 18微米）之SKI-606調配物的影響。據觀察，即使在開放盤中處於苛刻穩定條件下，溶解移位似乎亦可忽略不計。圖17匯總了 API粒徑對含有聚氧乙烯山梨醇酐單油酸酯 (Tween-80)之SKI-606調配物之旋劑溶解作用沒有影響。圖1 8匯總了 500 mg強度基於交聯羧甲纖維素之調配物 (2%黏合劑及2%粒内及粒外CCS)在加速穩定狀態下在具有乾燥劑之瓶中之溶解作用，其中500 mg經塗覆調配物存於具有乾燥劑之瓶中。在6 Μ及40°C/75% RH下未觀察到溶解移位。圖19匯總了 500 mg強度基於交聯羧甲纖維素之調配物 (2%黏合劑及2%粒内及粒外CCS)在加速穩定狀態下在沒有乾燥劑之瓶中之溶解作用，其中500 mg經塗覆調配物存於具有乾燥劑之瓶中。在6 Μ及40°C/75% RH下，觀察到溶 149415.doc -49- 201113050 解移位極少。圖20匯總了 500 mg強度基於交聯羧曱纖維素之調配物 (2%黏合劑及2%粒内及粒外CCS)在加速穩定狀態下在具有乾燥劑之瓶中之溶解作用，其中1〇〇 mg經塗覆調配物存於具有乾燥劑之瓶中。在6 Μ及40t： /75% RH下，未觀察到溶解移位。圖21A匯總了按比例放大（100 Kg)批料在具有乾燥劑之瓶中之溶解穩定性。在CTAB/乙酸鹽緩衝液中在穩定狀態下溶解作用具有最小至沒有移位（A)且在0.1 N HC1中沒有移位（B)。 149415.doc 50-Claim: 69.0% Batch: 25 Kg Ingredient function based on spinner core based on intragranular solids input/dosage unit (for 500 mg engraved intensity) Involvement/dosage unit (for 100 mg dose strength) —-— Representative peach Formulation % wt/wt % wt/wt Input unit input position ---^ Involve unit SKI-606 monohydrate, equivalent to anhydrous active agent 68.96 83.6 500 mg 100.0 mg --- 17.241 Microcrystalline cellulose (PH101 Filler 6.50 7.9 47.1 mg 9.420 mg1 ~L62A~ ------ Kg croscarmellose nanodisintegrator 2.0 2.4 14.49 mg 2.898 mg 0.500 Kg Poloxamer 188 Wetting agent 3.0 3.6 21.74 mg 4.348 Mg 0.750 Kg Povidone, K-25 Binder 2.0 2.4 14.49 mg 2.898 mg 0.500 Kg Purified water b Granulation solution QS QS 241.86 mg 48.37 mg 8.340 Kg Total 82.46 100 597.820 mg 119.564 mg 20.615 Kg Dry blend and coated Layer Section: Table 6. Dry Blend and Coated SKI-606 Formulations Component Function Based on Lozenge Core, % wt/wt Input/Dose Unit Input (500 mg) Input/Dose Unit Input Early (100 mg) Representative batch Square wheel into unit drying SKI-606 granulation part ΝΑ 82.46 597.820 119.564 mg 20.615 Kg microcrystalline cellulose (PH 102) filler 15.042 109.055 21.811 mg 3.761 Kg 149415.doc -34· 201113050 croscarmellose sodium disintegration Agent 2.0 14.5 2.900 mg 0.500 Kg Magnesium stearate lubricant 0.5 3.625 0.725 mg 0.125 Kg Total 100.0 725.00 145.000 mg 25.0 Kg Coated Opadry-II yellow, 85F12390 Coating agent 3.0 NA 4.350 mg 0.975 Kg Opadry-II red, 85F15642 21.75 NA Purified Water Coating Carrier QS 123.25 24.650 mg 5.525 Kg Total 103.0 746.75 149.350 mg 6.5 Kg Prepared SKI-606 formulation and coated tablets of SKI-606 formulation as follows: Preparation procedure is as follows To prepare a coated tablet of the SKI-606 formulation and the SKI-606 formulation: The following ingredients were weighed in a 25 Kg batch: SKI-606 monohydrate 17.241 Kg Microcrystalline cellulose (Avicel PH 101) 1.624 Kg Sodium carboxymethylcellulose 0.5 Kg Povidone K-25 0.5 Kg Poloxamer 0.75 Kg 1. The povidone and poloxamer are dissolved in purified water. 2_Add the intragranular fraction of SKI-606, microcrystalline cellulose (PH 101), and croscarmellose sodium to the high shear granulator with a minimum of 4 minutes. •35- 149415.doc 5- 201113050 Buckle 'or until uniform. If desired, the dried ingredients can be sieved to remove agglomerates prior to pre-doping. 3. At the same time, add the step 1 solution to the high shear granulator and mix until the appropriate granules are achieved. If necessary, adjust the amount of water to achieve a satisfactory granulation endpoint. 4. As needed, the granules may be passed through a mill or sieve to promote granulation before drying. 5. Dry the granules in a fluidized bed to dry until the desired end point is reached. At this time, the L〇D at the test temperature should be less than 3〇/〇 w/w, where the target is 1 -1.5% w/w. 6_ The dried granules are passed through a mill equipped with a suitable screen or screen to promote a satisfactory particle size distribution for blending. Leave this section for step 10. 7. Add the granules to a suitable blender. If necessary, mix the dried graded granules for a minimum of 5 minutes or until uniform. 8. Calculate the amount of extragranular components based on the yield obtained from the dried granules. 9. The dry blend component can be sieved and subsequently blended. If desired, the microcrystalline cellulose sample is retained for blending in step 1 . Microcrystalline cellulose and croscarmellose sodium were added to the mixer and blended for 10 minutes or until homogeneous. 10. Add a portion of the particles from step 6 or microcrystalline cellulose from step 9 (pH 102) to magnesium stearate and mix to form a lubricant pre-batch. The lubricant preblend is added to the Step 9 blender and mixed for a minimum of 2 minutes, or until uniform. 149415.doc •36· 201113050 11. Use suitable tools to compress the particles at the appropriate hardness. Preparation and application of a coating suspension 1. If necessary, the dried pigment is sieved prior to mixing. Purified water is added to the pigment coating using a suitable mixer and can and mixed until a satisfactory suspension is formed. The suspension can be sieved through a suitable sieve. 2. Apply 5 Kg of coating suspension to the bed for a total weight gain of 3% wt/wt. This can be confirmed by the weight gain of the tablet, if desired. Table 7: SKI-606 formulations with crospovidone disintegrants. Coated tablets at different unit doses. Example ingredients Qty (Q w/%) of the weight of the core of the core. Qty/ Tablets (mg) 500 mg dose of Qty/synthesis agent (mg) SKI 606 monohydrate (based on 96% analysis) 69 104.17 520.83 Avicel pH 101 7.5 6.7 33.52 crospovidone 1.0 1.45 7.25 poloxamer -188TM 3.0 4.35 21.74 Povidone 2.0 2.9 14.49 Water QS Extragranular ingredient crospovidone 3.0 4.35 21.74 Avicel pH 101TM 14.0 20.29 101.45 Magnesium stearate 0.5 0.724 3.62 Total weight of uncoated bond (mg) 145.0 725.0 Opadry II Yellow 85F12390 ' 4% w/w 6.04 — Opadry II Red 85F15642 85F12390, 4% w/w ~ 30.19 Total lozenge weight (mg) of coated lozenges 151.04 755.19 149415.doc -37- 201113050 The coated SKI-606 formulation in batches of 1 Kg core tablet and the coated sharpener of the SKI-606 formulation were prepared: The following ingredients were weighed: SKI-606 monohydrate 718.4 g microcrystalline cellulose (Avicel PH 101) 46.23 g crospovidone 10.0 g povidone oxime 25 20.00 g poloxamer 188 30.00 g 1. SKI-606, microcrystalline cellulose and crospovidone from step 1 are passed through a 20 mesh screen and the ingredients are added to a high shear mixer. 2. Mix the ingredients in Step 2 in a high shear granulator for 2 minutes at low single speed (impeller only). 3. Dissolve poloxamer ι88 and povidone ruler _25 in purified water in another mixer. Use a low mixer speed to avoid foam formation. 4. Set the impeller and chopper speed to a low setting. The solution from step 4 was added using a pump to granulate the mixture in step 3. If it is necessary to continue to mix for 2-5 minutes at low speed using a chopper and impeller when depleting the granulation solution. If necessary, add additional purified water while mixing until the granulation end point is reached. Check the desired granulation endpoint. If feasible, record the total amount of water used for granulation and total mixing time as well as power or torque readings. 5. Dry the granules in a fluid bed dryer with a recommended inlet temperature of 149415.doc -38 · 201113050 70 °C ± 5 °C for the recommended L.O.D. range of 丨 to 2.5%. Weigh and record the output. 6. Pass the dry granules through c〇mil at low speed (recommended mill speed is rpm or lower and the recommended sieve is 2 〇 mesh). Weigh and record the production &quantity; .00 final blending: , $ 7. Calculate the amount of ingredients required for the addition of (extragranular) dry addition based on the yield in step 7. 8. Add the abrasive particles from step 9. Transfer to a blender of appropriate size. 〇9· Weigh microcrystalline cellulose (PH 1〇1), leave the mixture and pass it through the mesh screen and add it to the V-blender in step n. Blend for 10 minutes without the action of the reinforcing rod. 1 〇·Mine the magnesium stearate through the 3 〇 mesh screen and bag-mix with the particles of the same part of step i 2 and add to the ¥_ blend In the case of the device, it is blended for 2 minutes without the reinforcing rod. 曰11· Weigh and record the yield. Press the tablet of known weight and hardness and apply the film to the pressed tablet. In one example, the SKI_606 formulation of the present invention eliminates one or more of the problems associated with solid-based salivary solid formulations, such as certain SKI_606 formulations when tested under buffered or acidic conditions (see comparison). Sexual examples) The dissolution can be changed at room temperature and under accelerated conditions and the post-aging/glutinability can be A small but significant shift occurred, as summarized in Figures 1 and i 2. Figure 11 shows that the solubility of the cross-linked carboxycellulose formulation did not shift. Figure 12 shows the dissolution shift of the existing formulation. SKI_606 pairs 149415.doc 39· 201113050 The ratio of the sam 188 in the specific formulation causes the observed dissolution shift. The poloxamer is close to its melting point despite being solid at room temperature. Liquefaction often occurs at and around the temperature of 48-52 C. The studies summarized in Figures 13 and 14 show that the pois/sam-based tablets in the formulation of crospovidone are dissolved and displaced. The real reason. In some embodiments, different amounts of poloxamer (〇, 15% w/w, 3% w/w, 4 5% w/wA 6% w/w, based on SKi 6〇6) are used. The weight of the formulation) was used to prepare a SKI_6〇6 tablet formulation. Unexpectedly, it was observed that the dissolution of the tablet was significantly dependent on the percentage of poloxamer in the formulation when tested in 〇·1 N HC1. Figure 13. Figure 13 summarizes the different poloxamer content ingots in 〇丨N HQ at similar water and viscosity addition rates. Effect of dissolution of the agent. It has been observed that poloxamer can only interfere with the release of the tested tablets, especially at earlier points in time. Poloxamer appears to be hampered in a concentration-dependent manner at 15 and 30 minutes. Initial tablet dissolution. See Table 8. SKI-606 with different poloxamer content 500mg spinner core disintegration time in 0丨N HC1 poloxamer concentration DoE-1/test number lozenge DT Range 丨N=6)(min) 0 -—~~~~~_____ 2 6.2-6.6 1.5 1 10.6-12.9 3.0 3 11.5-13.1 4.5 7 14.1-15.6 6.0 5 14.3-14.9 Despite the Poloxas in the lozenge At the initial stage, it is easy to hinder the dissolution, but it is found that it accelerates the dissolution of the 1494l5.doc •40·201113050 solution in the accelerated steady state at a later time point in the N. 1 N HC1 medium, as summarized in Table 9. Seen. Table 9: Increase in the percentage of dissolution of D〇E batch in NH.1NHC丨 and pH4 buffer (stabilized water (G) binder addition rate (g/min) poloxamer (% w/w) at 0.1 Release at 15 minutes in N HC1 (%> (+ increase in % dissolution compared to the initial) 147 58.5 0 Initial 66 1M at +3 1M at 40 °C at 40 °C / 75 ° / 〇 +6 162 58.5 under RH 1.5 Initial 50 1M, +19 1M at 40°C, +22 147 58.5 3.0 at 40°C/75% RH Initial 43 1M, +11 1M at 40°C, at 40° +31 158 66 at C/75% RH 4.5 Initial 38 1M, +13 1M at 40°C, +8 147 58.5 at 40°C/75% RH Initial 38 1M, +6 1M at 40°C , at 40 ° C / 75% RH +14 Under accelerated steady state, poloxamer caused a dissolution shift from 0 % w/w to 3% w / w in a concentration-dependent manner. At %, the poloxamer concentration tends to be stable without a significant tendency. These results confirm that the poloxamer can cause a dissolution shift in a steady state. It is believed that the poloo after aging and at the accelerated temperature The sam chain becomes Easy to move, and thus instead of holding the particles together in the lozenge, the mobile polymer chain tends to "soften" the bond. This situation may be, the core particles are at any time (four) and collapse The trend of solution has increased. It has also been found that * soft reduction. - Once the tablet has disintegrated, (4) The time of the 2nd state is different. The particles in the tablet are actually similar to all known surfactants. "> Ding Feng increases the surfactant to increase the particle dissolution, as seen in Figure 14. The S°-606 formulation of the present invention eliminates this dissolution shift problem, and the complex is replaced by the formulation. Used as a wetting agent for surfactants, poloxamer. The use of lower melting point surfactants (liquid at room temperature) can help solve this problem. Polyoxyethylene (20) sorbitol Hepatic monooleate (TweenTM or polysorbate 80, one of the commonly used surfactants. Polyoxyethylene (20) sorbitan monooleate (IV) polyoxyethylene sorbitol mono-oil tested in the formulation The concentration of sour vinegar (Tween-80) is 1% (instead of 3% poloxamer). This can be used in a cpv formulation with 3% IG and 1% EG CPV as a disintegrant. We believe this is acceptable because the dissolution and other manufacturability characteristics tested under this indifference are acceptable. In addition, polyoxyethylene sorbitan monooleate (Tween_8®)TM is a commonly used pharmaceutically acceptable wetting agent and is also used as a surfactant. In addition to addressing the dissolution shift, it is desirable to test the stability of the formulations in terms of active pharmaceutical ingredient API particle size. In the comparative SKI_6〇6 formulation, the API particle size appears to affect the dissolution, that is, the smaller the particle size, the slower the dissolution. For SKI/Tween-80 formulations, this effect can be minimized or negligible (Figure 17) and includes the alternative wetting agent polyoxyethylene sorbitan monooleate (Tween-80)TM for SKI_606 formulations in Chen The comparison (Figures 5 and 16) is superior to the comparative SKI-606 formulation. 149415.doc • 42-201113050 Examples 11 and 12: Preparation of a pharmaceutically acceptable composition of SKI-606 SKI was prepared according to the method detailed in one or more of U.S. Patent Nos. 6,297,258 and 7,297,795. -606. Exemplary SKI-606 formulations and comparative SKI-606 formulations of the present invention are summarized in Table 10. Table 10. SKI-606 formulation intragranular component SKI-606 formulation 1 comparative SKI-606 tune SKI-606 replacement surface ligand active agent formulation (% w/w) (% w/w) (% w /w) SKI-606 monohydrate, equivalent to SKI-606 base 69 69 69 microcrystalline cellulose (MCC, Avicel PH101) 6.5 17.5 19.5 crospovidone (CPV) ΝΑ 3 3 croscarmellose sodium (CCS) 2 ΝΑ 泊 Poloxamer 188TM (Lutrol F-68TMTM) 3 3 聚 Polyoxyethylene sorbitan monooleate (Tween -80) 1 Povidone (Kollidon 25) 2 2 2 Weight % of internal component 82.5 94.5 94.5 Extragranular ingredient Microcrystalline cellulose (MCC, Avicel 101TM) ΝΑ 4 4 Microcrystalline cellulose (MCC, Avicel 102TM) 15 ΝΑ 交交维维 ΝΑ 1 1 Crosslinked carboxy Methylcellulose sodium 2 ΝΑ 镁 Magnesium stearate 0.5 0.5 0.5 Weight percent of extragranular component 17.5 5.5 5.5 Coating (Opadryll system) 3 4 4 149415.doc •43- 201113050 ΝΑ- Not applicable or not available including polyoxygen Alternative SKI-606 formulations of ethylene sorbitan monooleate (Tween_8®) as a wetting agent are summarized in Tables 1-13. Table 11. Alternative SKI-606 formulations including poly(ethylene sorbitan) monooleic acid g (Tween-80) and different crospovidone concentrations ο Ingredient alternative Tween formulation (% w/w) Alternative Tween formulation (% w/w) Alternative Tween formulation (% w/w) SKI-606 monohydrate, equivalent to SKI-606 base 69 69 69 Microcrystalline cellulose (MCC, Avicel PH101) 21.5 20.5 18.5 Crospovidone (CPV) 1 2 4 Cross-linked sodium carboxycellulose (CCS) ΝΑ ΝΑ ΝΑ Tween-80TM 1 1 1 Kollidon 25TM 2 2 2 Weight of the intragranular component. /〇94.5 94.5 94.5 Microcrystalline cellulose (MCC, Avicel 101) 2 3 5 crospovidone 3 2 0 Magnesium stearate 0.5 0.5 0.5 Weight of extragranular component ° / 〇 5.5 5.5 5.5 149415.doc • 44· 201113050 Table 12 - Alternative SKI-606 formulations comprising different levels of polyoxyethylene sorbitol gf monooleic acid (Tween-80). Ingredients Alternative Tween Alternative Tween Alternative Tween Formulation Formulation (% w/w) (% w/w) (% w/w) SKI-606 monohydrate, equivalent to SKI-606 base 69 69 69 microcrystalline cellulose (MCC, Avicel PH 101) 20 20.25 19.75 crospovidone (CPV) 3 3 3 croscarmellose sodium (CCS) ΝΑ ΝΑ ΝΑ Tween-80TM 0.5 0.25 0.75 povidone (Kollidon25 2 2 2 % by weight of intragranular component 94.5 94.5 94.5 microcrystalline cellulose (MCC, Avicel 101) 4 4 4 crospovidone 1 1 1 magnesium stearate 0.5 0.5 0.5 weight fraction of extragranular component 5.5 5.5 5.5 149415.doc -45· 201113050 Table 13. Alternative SKI-606 formulations comprising polyoxyethylene sorbitan monooleate (Tween_8®) with different binder concentrations. Ingredients -------- Alternative Tween Alternative Tween Alternatives ^^ Ingredients Formulations (% W/W) (% w/w) ί〇/„ w/w) SKI-606 Monohydrate, equivalent to SKI-606 base 69 69 69 microcrystalline cellulose (MCC, Avicel PH101) 20.5 19.5 18.5 crospovidone (CPV) 3 3 3 croscarmellose sodium (CCS) ΝΑ ΝΑ ΝΑ Tween-80TM 1 1 1 Povidone (Kollidon25) 1 2 3 Weight % of intragranular component 94.5 94.5 94.5 Microcrystalline cellulose (MCC, Avicel 101) 4 4 4 Crospovidone 1 1 1 Magnesium stearate 0.5 0.5 0.5 wt% of the extra-fraction component 5.5 5.5 5.5 A comparative SKI-606 formulation was prepared by the following procedure: high shear wet granulation 'wet grinding, fluidized bed drying, dry milling, blending and pressing Tableting agent, followed by coating of the film. In certain embodiments, the SKI-606 formulation of the present invention comprises a SKI-606 formulation of a coated film prepared by high shear wet granulation or disc coating. In other embodiments, the coated film of the SKI-606 tablet formulation is prepared by other conventional coating techniques. [Simplified Schematic] 149415.doc -46- 201113050 Figure 1 summarizes the differences The dissolution rate of the tablet of the SKI-606 formulation of the solvent (croscarmellose sodium versus crospovidone). Figure 2 summarizes the dissolution of the SKI-606 formulation containing crospovidone under accelerated steady state. In particular, the tablet appears to have a significant dissolution shift especially at earlier points in time. Figure 3 summarizes the dissolution of the SKI-606 formulation containing croscarmellose sodium in an accelerated steady state. To shift (compared to Figure 2) Figure 4 summarizes the effect of different intragranular and extragranular (IG and EG) croscarmellose sodium concentrations on the dissolution rate of tablets in SKI-606 formulations. 5 summarizes the effect of different intragranular and extragranular (IG and EG) crospovidone concentrations on the dissolution rate of the tablets in the SKI-606 formulation. A wide dissolution can be observed here, indicating that the dissolution is The concentration dependence of the ratio of crospovidone. The dissolution of the formulation containing D90 API appears to be significantly different from that of other APIs containing D90 = 40 or 60 microns. Figure 6 summarizes the active pharmaceutical ingredient (API) particle size pairs. Contains crospovidone and contains 2% binder, and 2% intragranular and extragranular Effect of the dissolution of the SKI-606 formulation of the decomposing agent. Figure 7A and B summarize the API particle size distribution in the CTAB/acetate and 0·1 N HC1 medium for SKI-606 based on carboxylated cellulose sodium. Things have no effect. The CTAB/acetate medium is considered to be a more discriminating medium than the N1 N HC1. Comparing this figure with Figures 9 and Β, Figure 9 and Β can significantly demonstrate the different effects of API particle size on the dissolution of tablets based on crospovidone formulations. Figure 8 summarizes the SKI-606 formulation based on cross-linked carboxycellulose (test 149415.doc • 47·201113050 A, B and C) for tablet hardness (in the range of 120·190 Ni) without dissolution dependence' This demonstrates the solubility stability of the formulation. In a preparation device, it may often be necessary to vary the tablet hardness and this formulation clearly provides this ability. Figures 9 and 8 summarize the effect of API particle size on the dissolution of crospovidone-based formulations in tablets (100 and 500 mg strength) in ι η N HC1. Compare and contrast this figure with Figures 7a and 7B which do not show this dependency. Figure 〇〇〇〇〇 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 Dissolution data for the formulation of the percentage of the agent and the ratio of the disintegrant. Significant dissolution differences were observed early in the dissolution of the two batches of the tablet, indicating no solubility reproducibility under accelerated steady state. Comparing and comparing this formulation with a graph] A formulation based on cross-linked carboxycellulose sodium that does not exhibit any difference in a steady state. ~ Figure 11 summarizes the formulation based on cross-linked celluloid steel (ccs) without any dissolution shift under steady state conditions similar to the batch of crospovidone (cpv) in Figure 10. Figure 12 shows the (10) and the composition of the cross-linked vitamin (cpv) SKI_6〇6 formulation! (8) Additional dissolution shift of post-strength lozenges in Q1 NHC1 under accelerated aging conditions. The two intrinsic strengths of the two strengths observed in 0.1 N HC1 have a consistent upward trend. " Figure 13 summarizes the comparative dissolution profiles of SKI.606 formulations with different concentrations of wetting agent (poloxamer). It has been observed that poloxamer has an unexpected effect of reducing the dissolution of the tablet in a concentration dependent manner. 149415.doc •48· 201113050 Figure 14 summarizes the effect of wetting agents on the dissolution of particles in the SKI-606 formulation. This effect demonstrates that increasing the poloxamer concentration increases the particle dissolution. Figure 15 summarizes the accelerated ageing at 40 ° C and 40 ° C / 75% RH open tray for 6 weeks to contain polyoxyethylene sorbitan monooleate (Tween-80) as a wetting agent (API D9G) = 38 μm) of the effect of the SKI-606 formulation. It has been observed that even under the harsh conditions of open discs, the displacement seems negligible. Figure 16 summarizes the accelerated dishing conditions at 40 ° C and 40 ° C / 75% RH for 6 weeks to contain polyoxyethylene sorbitan monooleate (Tween-80) as a wetting agent (API D9〇) = 18 μm) of the effect of the SKI-606 formulation. It has been observed that even in harsh and stable conditions in open discs, the dissolution shift seems to be negligible. Figure 17 summarizes that API particle size has no effect on the dissolution of the SKI-606 formulation containing polyoxyethylene sorbitan monooleate (Tween-80). Figure 1 8 summarizes the dissolution of a 500 mg strength croscarmellose-based formulation (2% binder and 2% intragranular and extragranular CCS) in a desiccant bottle under accelerated steady state, A 500 mg coated formulation was stored in a vial with a desiccant. No dissolution shift was observed at 6 Torr and 40 ° C / 75% RH. Figure 19 summarizes the dissolution of 500 mg strength based on croscarmellose-based formulations (2% binder and 2% intragranular and extragranular CCS) in accelerated steady state in bottles without desiccant, 500 The mg coated formulation is stored in a vial with a desiccant. At 6 Μ and 40 ° C / 75% RH, it was observed that the dissolution of 149415.doc -49- 201113050 was minimal. Figure 20 summarizes the dissolution of a 500 mg strength based on a crosslinked carboxyindole cellulose formulation (2% binder and 2% intragranular and extragranular CCS) in a desiccant bottle under accelerated steady state, 1 The 〇〇mg coated formulation was stored in a vial with a desiccant. At 6 Μ and 40t: /75% RH, no dissolution shift was observed. Figure 21A summarizes the solubility stability of a scaled up (100 Kg) batch in a vial with a desiccant. The dissolution in the steady state of CTAB/acetate buffer has minimal to no shift (A) and no shift in 0.1 N HC1 (B). 149415.doc 50-

Claims

201113050 VII. Patent Application Range: 1. A pharmaceutically acceptable composition comprising: an intragranular component (a) from 20 to 80% by weight, based on the weight of the composition, of 4-(2,4-di Gas-5-decyloxy-phenylamino)-6-methoxy-7-[3-(4-methyl-hexahydro.pyrazine-1-yl)-propoxy; base]-喧-3 - carbonitrile; (b) povidone; (c) microcrystalline fiber; (d) 0.25 to 5% by weight, based on the weight of the composition, of crosslinked methacrylate sodium; (e) poloxamer; and extragranular component (f) microcrystalline cellulose; and (g) magnesium stearate. 2. A pharmaceutically acceptable composition comprising: an intragranular component (a) from 25 to 80% by weight, based on the weight of the composition, of 4-(2,4-dioxa-5-decyloxy) _ Benzylamino)-6-decyloxy-7-[3-(4-indolyl-hexahydro) 嗓_1_yl)-propoxy]-quinoline-3-carbonitrile; (b Povidone; (c) microcrystalline cellulose; (d) from 0.25 to 5% by weight, based on the weight of the composition, of crosslinked methacrylate sodium; (e) poloxamer; Extragranular component (7) microcrystalline cellulose; and (g) magnesium stearate. 3' The composition of claim 1, wherein 4_(2 4 monochloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-A) is based on the weight of the composition The amount of quinone-hexanitroindole-l-yl-1-yl)-propoxy]-quinoline-3-carbonitrile was about 69% by weight. 4. The composition of any one of claims 1 to 3, wherein the amount of the heavy star β10' crosslinked tremor cellulose sodium in the intragranular portion of the composition is about 1 to 3 weights. /〇. 5. The composition of any one of claims 1 to 3, wherein the amount of croscarmellose sodium in the extragranular portion is from the weight of the composition, 』1 to 3 weight 149415.doc 201113050 The composition of claim 1 wherein the amount of the povidé is about 2% by weight based on the weight of the composition. The composition of Moonament Item 1, wherein the amount of microcrystalline cellulose is about 21.5% by weight based on the weight of the composition. 8. The composition of claim 7, wherein the amount of microcrystalline cellulose in the granules is 'about 65 weight ❶> by weight of the composition; or the weight of the composition The amount of microcrystalline cellulose as the extragranular component is about 1 $1% by weight or both. 9. A composition as claimed, wherein the amount of poloxamer is about 3 weights per ounce based on the weight of the composition. The composition of the present invention, wherein the amount of magnesium stearate is about 0.5% by weight based on the weight of the composition. 11. A pharmaceutically acceptable composition for oral administration comprising: an intragranular component, (a) 25 to 80% by weight, based on the weight of the composition, of 4-(2,4- Dichloro-5-methoxy-phenylamino)_6_methoxy_7·[3_(4methyl-hexahydropyrazine-1-yl)-propoxy]-quinoline_3· (b) 〇 5 to 5 〇 weight 0 / 聚 polydimensional _; (c) 1 to 25% by weight of microcrystalline cellulose; (d) 5 5 to 5 % by weight of crosslinked carboxymethyl fiber Sodium; (e) 〇2 to 5% by weight of poloxamer, and extragranular component, ten (1) 1 to 25 mil % of microcrystalline cellulose by weight of the uncoated/core tablet composition; (g) 〇5-5 wt% of crosslinked bismuth cellulose sodium; and (h) 0.5-5 wt% of stearic acid. 1 2. The composition of claim 8, wherein 4_(2 4_mono-5-methoxy-phenylamino)-6-methoxy_7_[3-(4- The amount of methyl-hexahydropyridinazine-1-yl)-propoxy]-quinoline-3-carbonitrile was about 69 wt./〇. 149415.doc -2 - 201113050 13. The composition of claim 2 or 2, wherein the amount of paclitaxel sodium in the intragranular portion is from about 丨 to 3 by weight of the composition weight%. 14. The composition of claim 丨丨 or 丨], wherein the amount of crosslinked strontium methylcellulose in the extragranular portion is from about 丨 to 3% by weight based on the weight of the composition. 15_ The composition of claim , wherein the amount of povidone is about 2 weight ❶/ by weight of the composition. The amount of microcrystalline cellulose is about 21.5 wt% based on the weight of the composition; the amount of poloxamer is about 3% by weight based on the weight of the composition; or by weight of the composition, The amount of magnesium stearate is about 0.5% by weight. The composition of claim 5, wherein the amount of microcrystalline cellulose as the intragranular component is about 65% by weight based on the weight of the composition. The amount of microcrystalline cellulose as the extragranular component is about 15% by weight, or both, based on the weight of the composition. 17. A pharmaceutically acceptable composition comprising: an intragranular component, 25 to 80% by weight, based on the weight of the composition, of 4_(2,4_digas·5-methoxy-phenyl) Amino)-6-methoxy-7-[3-(4-mercapto-hexahydropyridazine "- kibpropoxy phthalocyanine-3-carbonitrile, and 重量25 by weight of the composition Up to 5% by weight of croscarmellose sodium; and an extragranular component, optionally including microcrystalline fibroin; and magnesium stearate. 18. The composition of claim 1 or 11, which is 4_ (2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-indolyl-hexahydropyridazine-indolyl)-propoxy] Oral suspension form of phthalocyanine-3 -carbonitrile 19. The composition of claim 1 or 11 which is in the form of a wet granulation, a film coated tablet, or in the form of a disc coated tablet. S 149415.doc 201113050 20. A method of treating cancer comprising administering an effective amount of a composition as claimed in claim 1 or 11. H9415.doc