201233673 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種可用作爲藥物之包含喹啉衍生物的 藥學組成物。更特別地，本發明係關於一種改良唾啉衍生 物或其藥學可接受之鹽或其溶劑化物之溶解性的藥學組成 物。 【先前技術】 式（I)所示之喹啉衍生物或其藥學可接受之鹽或其 溶劑化物（下文中稱爲喹啉衍生物（I))已知具有強的 血管形成抑制效果（專利文獻1 )及c-Kit激酶抑制效果 (專利文獻2)且有用於作爲多種腫瘤（諸如甲狀腺癌、 肺癌、黑色素瘤、胰臟癌）之預防或治療劑，且作爲這些 腫瘤之轉移抑制劑=201233673 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a pharmaceutical composition comprising a quinoline derivative which can be used as a medicament. More particularly, the present invention relates to a pharmaceutical composition for improving the solubility of a saponin derivative or a pharmaceutically acceptable salt thereof or a solvate thereof. [Prior Art] The quinoline derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof (hereinafter referred to as quinoline derivative (I)) is known to have a strong angiogenesis inhibitory effect (patent Document 1) and c-Kit kinase inhibitory effect (Patent Document 2) and are useful as prophylactic or therapeutic agents for various tumors such as thyroid cancer, lung cancer, melanoma, pancreatic cancer, and as metastasis inhibitors of these tumors =
其中R1是氫原子、C!.6烷基或C3-8環烷基；且R2是氫原 子或甲氧基。 然而，已發現：當配製成藥學組成物時，喹啉衍生物 (I )在潮濕且溫暖之儲存條件下會降解。此外，當該藥 學組成物吸收水分時，由於在該組成物表面上之膠化作用 201233673 ，會延緩活性成分喹啉衍生物（I)由該藥學組成物溶解 。爲要克服這些問題，已發展一種藥學組成物，其包括喹 啉衍生物（I) 、（1) 一化合物（爲5% (重量/重量）之 水溶液或懸浮液且具有8或更高之pH )、及/或（2 )砂 酸、其鹽或其溶劑化物（專利文獻3)。 引用文獻之列示 專利文獻 專利文獻 1 : WO 2002/32872 專利文獻 2 : WO 2004/080462 專利文獻 3 : WO 2006/03 0826 【發明內容】 技術問題 然而，還想要發展出具有更優越之唾啉衍生物（I ) 溶解作用的藥學組成物。因此，本發明的目的是提供一種 即使在長期儲存後喹啉衍生物（I )仍保持優越的溶解作 用之藥學組成物。 問題之解決方法 本發明人已密集地硏究以解決以上問題，且令人驚訝 地已發現以下之構造可以解決上述問題且已完成本發明。 具體言之，本發明提供以下<1>至<12>。 [1] 一種藥學組成物，其包含 201233673 (1)式（I)所不之化合物或其藥學可接受之鹽或其 溶劑化物Wherein R1 is a hydrogen atom, a C..6 alkyl group or a C3-8 cycloalkyl group; and R2 is a hydrogen atom or a methoxy group. However, it has been found that the quinoline derivative (I) degrades under wet and warm storage conditions when formulated into a pharmaceutical composition. Further, when the pharmaceutical composition absorbs moisture, the active ingredient quinoline derivative (I) is dissolved by the pharmaceutical composition due to gelation on the surface of the composition 201233673. In order to overcome these problems, a pharmaceutical composition comprising a quinoline derivative (I), (1) a compound (in an aqueous solution or suspension of 5% (w/w) and having a pH of 8 or higher has been developed). And/or (2) oxalic acid, a salt thereof or a solvate thereof (Patent Document 3). CITATION LIST Patent Literature Patent Literature 1: WO 2002/32872 Patent Document 2: WO 2004/080462 Patent Document 3: WO 2006/03 0826 [Technical Problem] However, it is also desired to develop a superior saliva. The pharmaceutically acceptable composition of the morphological derivative (I). Accordingly, it is an object of the present invention to provide a pharmaceutical composition which retains superior dissolution of the quinoline derivative (I) even after long-term storage. Solution to Problem The inventors have intensively studied to solve the above problems, and surprisingly, it has been found that the following configurations can solve the above problems and have completed the present invention. Specifically, the present invention provides the following <1> to <12>. [1] A pharmaceutical composition comprising the compound of the formula (I) of the formula (I), or a pharmaceutically acceptable salt thereof or a solvate thereof;
其中R】是氫原子、C,.6烷基或<：3_8環烷基； 且R2是氫原子或甲氧基’及 (2 )鹼性物質。 [2] 依照[1 ]之組成物，其中該鹼性物質是碳酸鹽❶ [3] 依照[2]之組成物，其中該鹽是鹼土金屬鹽。 [4] 依照[3]之組成物’其中該鹼土金屬鹽是鎂鹽或鈣鹽 〇 [5] 依照[1]至[4]中任一項的組成物’其另外包含崩解劑 〇 [6] 依照[5]之組成物，其中該崩解劑是羧甲醚纖維素（ carmellose)鈉、錢甲酸纖維素錦' 錢甲基薇粉鈉、交聯 羧甲醚纖維素（croscarme丨lose )鈉、低取代之羥丙基纖 維素或交聯聚乙烯吡咯烷酮（crosPovidone)。 [7] 依照[1]至[6]中任一項的組成物’其中R1是氫原子， 甲基、乙基、正丙基或環丙基。 [8] 依照[1]至[7]中任一項的組成物’其中R1是環丙基。 [9] 依照[1]至[8]中任一項的組成物’其中R2是氫原子， 201233673 甲氧基、或乙氧基。 [10]依照[1]至[9]中任—項的組成物’其中R2是氫原子 〇 [11 ]依照[1 ]至[1 〇 ]中任一項的組成物，其中該藥學可接 受之鹽是氫氯酸鹽、氫溴酸鹽、對甲苯磺酸鹽、硫酸鹽、 甲磺酸鹽或乙磺酸鹽。 [12]依照[1]至[丨丨]中任一項的組成物，其中式（I )所示 之化合物是4- ( 3-氯-4·(環丙基胺基羰基）胺基苯氧基 )-7 -甲氧基-6-喹啉羧醯胺甲磺酸鹽。 本發明之有利效果 本發明之藥學組成物的主作用劑唾啉衍生物（I )具 有優越的溶解作用且在活體內具有優越之吸收作用。該藥 學組成物也是一種即使在長期儲存後仍能維持之藥學組成 物。 具體實例之描述 本發明之藥學組成物意指一種包含喹啉衍生物（I) 及鹼性物質作爲必要成分之組成物。該喹啉衍生物（I) 與該鹼性物質之混合比例一般是（但不限於）1 : 0.5至 5〇，較佳是1: 1至25，更佳是1: 2至12.5。 此外，該喹啉衍生物（I )相對該藥學組成物之總重 量（排除膠囊殼）的混合比例一般是0.25至50重量％ ’ 較佳是0.5至2 5重量％，更佳是1至1 2.5重量％。 -8- 201233673 該鹼性物質相對該藥學組成物之總重量的混合比例一 般是1至60重量％，較佳是5至50重量％，更佳是10至 40重量％。可將本發明之至少一種鹼性物質包括在該藥學 組成物中，或者也可包括二或多種鹼性物質。 該藥學組成物之劑量形式特別是指一種固態製劑，諸 如顆粒、細顆粒、錠劑、或膠囊等。較佳是細顆粒、顆粒 或塡充細顆粒或顆粒之膠囊。 該嗤啉衍生物（I)是在 WO 2002/32872中所揭示 之化合物。較佳之喹啉衍生物（I)是選自下列之喹啉衍 生物或其藥學可接受之鹽或其溶劑化物： 4- (3-氯-4-(環丙基胺基羰基）胺基苯氧基）-7-甲 氧基-6-唾啉羧醯胺， 4- (3-氯-4-(甲基胺基羰基）胺基苯氧基）-7-甲氧 基-6-喹啉羧醯胺， 4- (3 -氯- 4-(乙基胺基羰基）胺基苯氧基）-7 -甲氧 基-6-喹啉羧醯胺， N6-甲氧基-4- ( 3-氯-4-(((乙基胺基）羰基）胺基 )苯氧基）-7-甲氧基-6-喹咐羧醯胺’ 4-(3-氯- 4-(1-丙基胺基羰基）胺基苯氧基）·7_甲 氧基-6-喹咐羧醢胺， N6-甲氧基-4-(3-氯-4-(((環丙基胺基）羰基）胺 基）苯氧基）-7-甲氧基-6-喹啉羧醯胺’及 ^-甲氧基-4-(3-氯-4-(((乙基胺基）羰基）胺基 )苯氧基）-7-甲氧基-6-喹啉羧醯胺。 201233673 更佳之喹啉衍生物（I)是選自下列之喹啉衍生物或 其藥學可接受之鹽或其溶劑化物： 4- ( 3·氯-4-(甲基胺基羰基）胺基苯氧基）-7-甲氧 基-6-喹啉羧醯胺， 4- ( 3-氯-4-(乙基胺基羰基）胺基苯氧基）-7-甲氧 基-6-喹啉羧醯胺， 4-(3-氯- 4-(環丙基胺基羰基）胺基苯氧基）-7 -甲 氧基-6-喹啉羧醯胺， N6 -甲氧基-4- (3 -氯-4-(((環丙基胺基）羰基）胺 基）苯氧基）-7-甲氧基-6-喹啉羧醯胺，及 N6 -甲氧基-4·(3 -氯-4-(((乙基胺基）羰基）胺基 )苯氧基）-7-甲氧基-6-喹啉羧醯胺。 特佳之喹啉衍生物（I)是4-(3-氯-4-(環丙基胺基 羰基）胺基苯氧基）-7 -甲氧基-6-喹啉羧醯胺，或其藥學 可接受之鹽或其溶劑化物。 本發明之藥學可接受之鹽是指氫氯酸鹽、氫溴酸鹽、 對苯磺酸鹽、硫酸鹽、甲磺酸鹽或乙磺酸鹽。較佳是甲磺 酸鹽* 本發明之溶劑化物是指水合物、二甲基亞颯溶劑化物 、或乙酸溶劑化物。 該喹啉衍生物（I) 較佳是在WO 200 5/063 7 1 3中 所揭示之4- ( 3-氯-4-(環丙基胺基羰基）胺基苯氧基）· 7-甲氧基-6-喹啉羧醯胺之鹽的結晶，或其溶劑化物。特 佳之唾啉衍生物（I)是4-(3-氯_4-(環丙基胺基羰基） -10- 201233673 胺基苯氧基）-7-甲氧基-6-喹啉羧醯胺甲磺酸鹽之C型結 晶。 該喹啉衍生物（I)可用作爲多種腫瘤之預防或治療 劑且作爲腫瘤之轉移抑制劑。該喹啉衍生物（I)能有效 對抗之腫瘤的範例包括甲狀腺癌、非小細胞肺癌、黑色素 瘤、咽喉癌、食道癌、胃癌、結腸直腸癌、肝細胞癌、腎 細胞癌、胰癌、膀胱癌、乳癌、子宮癌、卵巢癌、前列腺 癌、睪九癌、胃腸道基質腫瘤、肉瘤、成骨肉瘤、血管瘤 、惡性淋巴瘤、骨髓白血病、神經瘤及神經膠瘤。 本發明之鹼性物質是指鹼性無機鹽。所述鹼性無機鹽 包括碳酸鈹、碳酸鎂、碳酸鈣、碳酸緦、碳酸鋇、碳酸鉀 、磷酸氫鈣、及氧化鈦。彼較佳是碳酸之鹼土金屬鹽，另 外較佳是碳酸鎂或碳酸鈣。 本發明之藥學組成物另外包括崩解劑，也是可接受的 。所述崩解劑包括玉米澱粉、部分預先凝膠化之澱粉、羧 丙基激粉、竣甲醒纖維素（carmellose)、翔甲酸纖維素 鈉、羧甲醚纖維素鈣、羧甲基澱粉鈉、交聯羧甲醚纖維素 (croscarmellose )鈉、低取代之羥丙基纖維素及交聯聚 乙烯吡咯烷酮（crospovidone)。彼較佳是交聯羧甲醚纖 維素鈉、低取代之羥丙基纖維素、或交聯聚乙烯吡咯烷酮 〇 本發明之藥學組成物可以藉由已知方法製備，諸如在 General Rules for Preparations in the Japanese Pharmacopoeia Fifteenth Edition 中所描述的方法製備。 -11 - 201233673 例如，在顆粒之情況中，可能視需要將賦形劑、黏合 劑、崩解劑、溶劑或類似者添加至該喹啉衍生物（I )以 進行攪拌製粒、擠出製粒、滾動製粒、流化床製粒、噴霧 製粒、或類似方式，且將其製備。也可接受地，用含有該 喹啉衍生物（I)及添加劑（諸如玉米澱粉、微晶纖維素 、羥丙基纖維素、甲基纖維素、或聚乙烯基吡咯烷酮）之 霧化劑塗覆，且同時將水或黏合劑（諸如蔗糖、羥丙基纖 維素或羥丙基甲基纖維素）之溶液噴灑，在核心材料（諸 如純化之蔗糖球粒、乳糖/結晶纖維素球粒 '蔗糖/澱粉球 粒或粒狀結晶纖維素）上。視需要進行定篩選及硏磨，也 是可接受的。 也可能另外視需要地將賦形劑、黏合劑、崩解劑、潤 滑劑、抗氧化劑、調味劑、著色劑、香料、或類似者添加 至以此方式所製備之顆粒並將之壓製成錠。可將所需之賦 形劑添加至該喹啉衍生物（I)，以直接將混合物壓製成 鍵。也可能將已添加/混合賦形劑（諸如乳糖、蔗糖、葡 萄糖、澱粉、微晶纖維素、粉狀甘草、甘露糖醇、磷酸鈣 物 生 衍 啉 喹 該 之 鈣 酸 硫 或 囊 膠 充 塡 粒 顆 之 彼 用 或 \»y 該賦形劑之範例包括乳糖、蔗糖、葡萄糖、果糖、澱 粉、馬鈴薯澱粉、玉米澱粉、小麥澱粉、米澱粉、結晶纖 維素、微晶纖維素、粉狀甘草、甘露糖醇、赤藻糖醇、麥 芽糖醇、山梨糖醇、海藻糖、矽酸酐、矽酸鈣、碳酸氫鈉 、磷酸鈣、無水磷酸鈣及硫酸鈣。 -12- 201233673 該黏合劑之範例包括明膠、澱粉、阿拉伯膠、黃蓍膠 、羧甲基纖維素、羥丙基纖維素 '羥丙基甲基纖維素、聚 乙烯基吡咯烷酮、甲基纖維素、部分預先膠化之澱粉、預 先膠化之澱粉、聚乙烯醇、精胺酸鈉、黏多糖及甘油。 該崩解劑之範例包括玉米澱粉、部分預先膠化之澱粉 、羥丙基澱粉、羧甲醚纖維素、羧甲醚纖維素鈉、羧甲醚 纖維素鈣、羧甲基澱粉鈉、交聯羧甲醚纖維素鈉、低取代 之羥丙基纖維素及交聯聚乙烯吡咯烷酮。 該潤滑劑之範例包括硬脂酸鎂、硬脂酸、硬脂酸鈣、 硬脂醯反丁烯二酸鈉、滑石及聚乙二醇（macrogol )。 該抗氧化劑之範例包括抗壞血酸鈉、L-半胱胺酸、亞 硫酸鈉、生育酚、及大豆卵磷脂。 該調味劑之範例包括檸檬酸、抗壞血酸、酒石酸、蘋 果酸、阿斯巴甜、阿色番（acesulfame )紳、索馬甜、糖 精鈉、甘草酸二鉀、麩胺酸鈉、5’-肌苷酸鈉及5’-鳥苷酸 鈉。 該著色劑之範例包括氧化鈦、三氧化二鐵、三氧化二 鐵黃、胭脂蟲紅、胭脂紅、核黃素、食品級黃色素5號及 食品級藍色素2號。 該香料之範例包括檸檬油、橘子油、薄荷腦、薄荷油 、冰片（borneol)及香草香料。 【實施方式】 本發明將在下文中參考實例作更詳細地描述，但不限 -13- 201233673 於這些實例。 實例1至3 使用高切變製粒機（設備名稱：FM-VG-10，Powrex Corporation製造），利用純水作爲溶劑，依照表1中之 配製比例，利用4- ( 3·氯-4-(環丙基胺基羰基）胺基苯 氧基）-7-甲氧基-6-喹啉羧醯胺甲磺酸酯之C型結晶（下 文中稱爲化合物A) 、D-甘露糖醇（商標名稱：Mannitol 'Merck )、沉澱的碳酸鈣（商標名稱：Whiton F， Shiraishi Calcium )、經丙基纖維素（HPC-L，Nippon Soda )、低取代之羥丙基纖維素（商標名稱：L-HPC ( LH-21) ，Shin-Etsu Chemical)、及微晶纖維素（商標名 稱：Ceolus PH-101，Asahi Kasei Chemicals)，進行濕式 製粒。藉由另外之乾燥將顆粒的水含量降至低於2%，並 使用篩選磨機（設備名稱：Power Mill P-04S，由Showa Giken KK製造）對該顆粒進行篩選，以使其顆粒直徑小 於1毫米。然後，依照表1中之配製比例，將微晶纖維素 (商標名稱:Ceolus PH-102 ’ Asahi Kasei Chemicals )及 滑石（商標名稱：Hi-Filler 17，Iwai Chemicals Company )添加至該經篩選的顆粒，且使用擴散（滾動型）混合機 (商標名稱:10L/20L Exchange-type Tumbler Mixer， Toyo Packing Corporation製造），將混合物充分混合。 在尺寸#4之硬膠囊內塡充100毫克之所得的顆粒以製備 含化合物A之膠囊。 -14- 201233673 [表1] 實例1 實例2 實例3 化合物A 1.25 5 12.5 沈澱之碳酸鈣 33 33 33 D-甘露糖醇 19.75 16 8.5 羥丙基纖維素 3 3 3 低取代之羥丙基纖維素 25 25 25 微晶纖維素(PH-101) 10 10 10 微晶纖維素(PH-102) 5 5 5 滑石 3 3 3 全部 100 100 100 單位:重量％ 實例4至9及比較例1至2 使用硏缽及杵，依照表2及表3中之配製比例，將化 合物A、沉澱的碳酸鈣、低取代之羥丙基纖維素、D_甘露 糖醇及滑石充分混合。在尺寸#3之硬膠囊內塡充100毫 克之所得的混合物以製備實例4至9之膠囊。也藉由相同 方法製備比較例1至2之膠囊，但其不含沉澱的碳酸鈣。 [表2] 比較例1 實例4 實例5 實例6 化合物A 5 5 5 5 沈澱的碳酸鈣 0 5 10 20 低取代之羥丙基纖維素 30 25 20 10 D-甘露糖醇 62 62 62 62 滑石 3 3 3 3 全部 100 100 100 100 單位:重量％ -15- 201233673 [表3] 比較例2 實例7 實例8 實例9 化合物A 20 20 20 20 沈澱的碳酸鈣 0 5 10 20 低取代之羥丙基纖維素 30 25 20 10 D-甘露糖醇 47 47 47 47 .滑石 3 3 3 3 全部 100 100 100 100 單位重量％ 測試實例1 在實例4至9及比較例1至2的膠囊內之 的溶解度依照在 Japanese Pharmacopoeia Edition中所述之溶解測試（the Paddle法，測 JP1溶液）被檢驗。結果，在不混合碳酸鈣之比 2的膠囊內之化合物A的溶解作用是不足的。相 混合碳酸鈣之實例4至9的膠囊內之化合物A 用則是良好的（圖1及圖2 )。 實例1 〇至1 5及比較例3至4 使用硏缽及杵，依照表4及表5中之配製比 合物 A、碳酸鎂（Kyowa Chemical Industry)、 羥丙基纖維素、D-甘露糖醇及滑石充分混合。 之硬膠囊內塡充100毫克之所得的混合物以製< 至15之膠囊。也藉由相同方法製備比較例3至 ，但其不含碳酸鎂。 化合物A Fifteenth 試介質： 較例1至 反地，在 的溶解作 例，將化 低取代之 在尺寸#3 唐實例1〇 4之膠靈 -16- 201233673 [表4] 比較例3 實例10 實例11 實例12 化合物A 5 5 5 5 碳酸鎂 0 5 10 20 低取代之羥丙基纖維素 30 25 20 10 D-甘露糖醇 "~~ 62 62 62 62 滑石 3 3 3 3 全部 100 r 100 Γ 100 100 單位:重量％ [表5] 比較例4 實例13 實例14 實例15 化合物A 20 20 20 20 碳酸錶 0 5 10 20 低取代内ά纖維桌 30 25 20 10 D-甘露糖醇 47 4*7 47 47 滑石 3 3 3 3 100 100 100 100 單位··重量％ 測試實例2 在實例1 〇至1 5及比較例3至4的膠囊內之化合物A 的溶解作用依照如測試實例1中之相同方法被檢驗。在不 混合碳酸鎂之比較例3至4的膠囊內之化合物A的溶解 作用是不足的。相反地，在混合碳酸鈣之實例10至15的 膠囊內之化合物A的溶解作用則是良好的（圖3及圖4) 實例1 6至1 7及比較例5至6 使用硏缽及杵，將純水添加至化合物A、沉澱的碳酸 鈣或碳酸鎂、羥丙基纖維素及交聯羧甲醚纖維素鈉（商標 名稱：Ac-Di-Sol，Asahi Kasei Chemicals)以進行製粒， 接著篩選乾燥之顆粒以使顆粒直徑小於1毫米。然後，依 -17- 201233673 照在表6中之配製比例，將微晶羥丙基纖維素（商標名稱 :Ceolus PH-102 · Asahi Kasei Chemicals )、低取代之經 丙基纖維素及滑石（商標名稱：Hi-Filler 17，Iwai Chemicals Company)添加至該經筛選的顆粒，且該混合 物充分地混合。在尺寸#4之硬膠囊內塡充100毫克之所 得的混合物以製備實例1 6至1 7之膠囊。也依照表7中之 配製比例，同樣地製備比較例5至6之膠囊，但其既不含 沉澱的碳酸鈣也不含有碳酸鎂，但含有甘露糖醇或滑石作 爲代替。 [表6] 實例16 實例17 化合物A 10 10 沈澱之碳酸鈣 15 0 碳酸鎂 0 15 羥丙基纖維素 2 2 交聯羥甲醚纖維素鈉 10 10 低取代之羥丙基纖維素 20 20 微晶纖維素(PH-102) 41 41 滑石 2 2 全部 100 100 單位湩量％ [表7] 比較例5 比較例6 化合物A 10 10 甘露糖醇 15 0 滑石 0 15 羥丙基纖維素 2 2 交聯羥甲醚纖維素鈉 10 10 低取代之羥丙基纖維素 20 20 微晶纖維素(PH-102) 41 41 滑石 2 2 全部 100 100 單位重量％ -18- 201233673 測試實例3 在實例16至17及比較例5的膠囊內之化合物a的 溶解作用依照如測試實例i中之相同方法被檢驗。在既不 混合碳酸鈣也不混合碳酸鎂之比較例5的膠囊內之化合物 A的溶解作用是不足的。相反地，在混合碳酸鈣或碳酸鎂 之實例16至17的膠囊內之化合物a的溶解作用則是良 好的（圖5 )。 測試實例4 將實例16至17及比較例6之膠囊在溫度60。(：之溫 度及7 5 %之相對溼度的條件下於開放系統中儲存丨星期， 接著利用高效能液體層析法測定降解物之產生。在既不混 合碳酸鈣也不混合碳酸鎂之比較例6的膠囊調和物中，降 解物之量增加。相反地，在混合碳酸鈣或碳酸鎂之實例 16至17的膠囊中，沒有觀察到降解物之增加（表8)。 [表8] 降解物(％) 定量的化合物A(%) 化合物A (起初） 1.61% 98.38% 比較例6 1.92% 98.08% _實例16 1.50% 98.50% »例17 1.57% 98.44% 實例1 8至1 9及比較例7至1 0 藉由與實例4至9及比較例1至2相同的方法，依照 表9及1 0之調和比例，將個別成分混合。在尺寸#3之硬 膠囊內塡充1〇〇毫克之所得的混合物以製備實例1 8至1 9 及比較例7至1 〇的膠囊。 -19- 201233673 [表9] 實例18 比較例7 比較例8 化合物A 20 20 20 ^澱的碳酸鈣 10 0 0 氧化鈣 0 10 0 氫氧化鈣 0 0 10 低取代之羥丙基纖維素 20 20 20 D-甘露糖醇 47 47 47 滑石 3 3 3 全部 100 100 100 單位:重量％ [表 10] 實例19 比較例9 比較例10 化σ物A 20 20 20 碳酸鎂 10 0 0 氧化鎂 0 10 0 氫氧化鎂 0 0 10 低取代之羥丙基纖維素 20 20 20 D-甘露糖醇 47 47 47 滑石 3 3 3 全部 100 100 100 單位:重量％ 測試實例5 在實例18至19及比較例7至1〇膠囊內之化合物a 的溶解作用藉由與測試實例1相同的方法檢驗。結果，在 混合氧化#5、氫氧化轉、氧化鎂或氫氧化鎂之比較例7至 10的膠囊內之化合物A的溶解作用是不足的。相反地， 在混合碳酸耗或碳酸鎂之實例18至19的膠囊內之化合物 A的溶解作用則是良好的（圖6及圖7 )。 工業上的應用性 依本發明之藥學組成物在喹啉衍生物之溶解作用上及 -20- 201233673 在安定性上是優越的，且因此可用作爲預防或治療腫瘤的 藥物。 【圖式簡單說明】 圖1顯示由實例4至6及比較例1中所得之組成物溶 解出化合物A的變化曲線。 圖2顯示由實例7至9及比較例2中所得之組成物溶 解出化合物A的變化曲線。 圖3顯示由實例丨〇至1 2及比較例3中所得之組成物 溶解出化合物A的圖形。 圖4顯不由貫例丨3至1 5及比較例4中所得之組成物 溶解出化合物A的變化曲線。 圖5顯示由實例1 6至1 7及比較例5中所得之組成物 溶解出化合物A的變化曲線。 圖6顯示由實例1 8及比較例7至8中所得之組成物 溶解出化合物A的變化曲線。 圖7顯不由實例1 9及比較例9至1 0中所得之組成物 溶解出化合物A的變化曲線。 -21 ·Wherein R] is a hydrogen atom, C, .6 alkyl or <:3-8 cycloalkyl; and R2 is a hydrogen atom or a methoxy group; and (2) a basic substance. [2] The composition according to [1], wherein the alkaline substance is carbonate ❶ [3] The composition according to [2], wherein the salt is an alkaline earth metal salt. [4] The composition according to [3] wherein the alkaline earth metal salt is a magnesium salt or a calcium salt 〇 [5] The composition according to any one of [1] to [4] which additionally comprises a disintegrating agent 〇 [ 6] The composition according to [5], wherein the disintegrant is sodium carmellose, cellulose glycolate, sodium ketone, croscarmellose (croscarme丨lose) Sodium, low substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone (crosPovidone). [7] The composition according to any one of [1] to [6] wherein R1 is a hydrogen atom, a methyl group, an ethyl group, a n-propyl group or a cyclopropyl group. [8] The composition according to any one of [1] to [7] wherein R1 is a cyclopropyl group. [9] The composition according to any one of [1] to [8] wherein R2 is a hydrogen atom, 201233673 methoxy group, or ethoxy group. [10] The composition according to any one of [1] to [9] wherein R2 is a hydrogen atom 〇 [11] according to any one of [1] to [1 〇], wherein the pharmaceutically acceptable The salt is a hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate. [12] The composition according to any one of [1] to [丨丨], wherein the compound represented by the formula (I) is 4-(3-chloro-4.(cyclopropylaminocarbonyl)aminobenzene Oxy)-7-methoxy-6-quinoline carboxamide methanesulfonate. Advantageous Effects of Invention The main agent of the pharmaceutical composition of the present invention, the sormine derivative (I), has a superior solubility and a superior absorption in vivo. The pharmaceutical composition is also a pharmaceutical composition that can be maintained even after long-term storage. DESCRIPTION OF THE EMBODIMENT The pharmaceutical composition of the present invention means a composition comprising a quinoline derivative (I) and a basic substance as essential components. The mixing ratio of the quinoline derivative (I) to the basic substance is generally, but not limited to, 1:0.5 to 5 Torr, preferably 1:1 to 25, more preferably 1:2 to 12.5. Further, the mixing ratio of the quinoline derivative (I) to the total weight of the pharmaceutical composition (excluding the capsule shell) is generally 0.25 to 50% by weight, preferably 0.5 to 25 % by weight, more preferably 1 to 1 2.5 wt%. -8- 201233673 The mixing ratio of the basic substance to the total weight of the pharmaceutical composition is generally from 1 to 60% by weight, preferably from 5 to 50% by weight, more preferably from 10 to 40% by weight. At least one basic substance of the present invention may be included in the pharmaceutical composition, or may also include two or more basic substances. The dosage form of the pharmaceutical composition refers in particular to a solid preparation such as granules, fine granules, lozenges, or capsules and the like. Preferably, the particles are fine particles, granules or capsules filled with fine particles or granules. The porphyrin derivative (I) is a compound disclosed in WO 2002/32872. The preferred quinoline derivative (I) is a quinoline derivative selected from the group consisting of pharmaceutically acceptable salts or solvates thereof: 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminobenzene Oxy)-7-methoxy-6-salrogline carboxamide, 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quin Carboxylaminium, 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4- (3-Chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinoxalinecarboxamide' 4-(3-chloro-4-(1) -propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoxalinecarboxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamine)) (carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide' and ^-methoxy-4-(3-chloro-4-(((ethylamino))) Carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide. 201233673 The preferred quinoline derivative (I) is a quinoline derivative or a pharmaceutically acceptable salt thereof or a solvate thereof selected from the group consisting of 4-(3·chloro-4-(methylaminocarbonyl)aminobenzene Oxy)-7-methoxy-6-quinolinecarboxamide, 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quin Carboxylaminium, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4 - (3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, and N6-methoxy-4· (3-Chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide. a particularly preferred quinoline derivative (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or A pharmaceutically acceptable salt or a solvate thereof. The pharmaceutically acceptable salt of the present invention means a hydrochloride, a hydrobromide, a p-toluenesulfonate, a sulfate, a methanesulfonate or an ethanesulfonate. Preferably, the mesylate salt * the solvate of the present invention means a hydrate, a dimethyl hydrazine solvate or an acetic acid solvate. The quinoline derivative (I) is preferably 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy). 7- disclosed in WO 200 5/063 7 1 3 Crystallization of a salt of methoxy-6-quinolinecarboxamide, or a solvate thereof. The particularly preferred porphyrin derivative (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)-10-201233673 aminophenoxy)-7-methoxy-6-quinolinecarboxylate Form C crystal of the amine mesylate. The quinoline derivative (I) can be used as a prophylactic or therapeutic agent for various tumors and as a metastasis inhibitor of tumors. Examples of tumors in which the quinoline derivative (I) is effective against thyroid cancer, non-small cell lung cancer, melanoma, throat cancer, esophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, Bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, sputum cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myeloid leukemia, neuroma and glioma. The basic substance of the present invention means an alkaline inorganic salt. The basic inorganic salt includes barium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, barium carbonate, potassium carbonate, calcium hydrogen phosphate, and titanium oxide. Preferably, it is an alkali metal carbonate, and further preferably magnesium carbonate or calcium carbonate. The pharmaceutical composition of the present invention additionally includes a disintegrant, which is also acceptable. The disintegrant comprises corn starch, partially pregelatinized starch, carboxypropyl powder, carmellose, sodium cellulose glycolate, calcium carboxymethyl ether, sodium carboxymethyl starch , croscarmellose sodium, low substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone (crospovidone). Preferably, it is croscarmellose sodium, low substituted hydroxypropylcellulose, or crosslinked polyvinylpyrrolidone. The pharmaceutical composition of the present invention can be prepared by known methods, such as in General Rules for Preparations in Prepared by the method described in the Japanese Pharmacopoeia Fifteenth Edition. -11 - 201233673 For example, in the case of granules, an excipient, a binder, a disintegrant, a solvent or the like may be added to the quinoline derivative (I) as needed for stirring granulation and extrusion. Granulation, rolling granulation, fluid bed granulation, spray granulation, or the like, and preparation thereof. Also acceptable, coating with an atomizing agent containing the quinoline derivative (I) and an additive such as corn starch, microcrystalline cellulose, hydroxypropyl cellulose, methyl cellulose, or polyvinylpyrrolidone And simultaneously spray a solution of water or a binder such as sucrose, hydroxypropylcellulose or hydroxypropylmethylcellulose in core material (such as purified sucrose pellets, lactose/crystalline cellulose pellets) / starch pellets or granular cellulose). Screening and honing as needed is also acceptable. It is also possible to additionally add an excipient, a binder, a disintegrant, a lubricant, an antioxidant, a flavoring agent, a coloring agent, a fragrance, or the like to the granule prepared in this manner and compress it into an ingot. . The desired excipient can be added to the quinoline derivative (I) to directly press the mixture into a bond. It is also possible to add/mix excipients (such as lactose, sucrose, glucose, starch, microcrystalline cellulose, powdered licorice, mannitol, calcium phosphate, sulphate or sulphur) Examples of the excipient include lactose, sucrose, glucose, fructose, starch, potato starch, corn starch, wheat starch, rice starch, crystalline cellulose, microcrystalline cellulose, powdered licorice , mannitol, erythritol, maltitol, sorbitol, trehalose, phthalic anhydride, calcium citrate, sodium hydrogencarbonate, calcium phosphate, anhydrous calcium phosphate and calcium sulfate. -12- 201233673 Example of the adhesive Including gelatin, starch, gum arabic, tragacanth, carboxymethyl cellulose, hydroxypropyl cellulose 'hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, methyl cellulose, partially pregelatinized starch, pre- Gelatinized starch, polyvinyl alcohol, sodium sulphate, mucopolysaccharide and glycerin. Examples of the disintegrant include corn starch, partially pregelatinized starch, hydroxypropyl starch, carboxymethyl ether cellulose, Methyl ether cellulose sodium, carboxymethyl ether cellulose calcium, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and cross-linked polyvinylpyrrolidone. Examples of the lubricant include hard Magnesium citrate, stearic acid, calcium stearate, sodium stearyl fumarate, talc and macrogol. Examples of such antioxidants include sodium ascorbate, L-cysteine, sodium sulfite , tocopherol, and soy lecithin. Examples of the flavoring agent include citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame, samar, sodium saccharin, dipotassium glycyrrhizinate, Sodium glutamate, sodium 5'-inosinate and sodium 5'-guanylate. Examples of the coloring agent include titanium oxide, ferric oxide, ferric oxide yellow, cochineal red, carmine, and nuclear yellow. , food grade yellow pigment No. 5 and food grade blue pigment No. 2. Examples of the fragrance include lemon oil, orange oil, menthol, peppermint oil, borneol and vanilla flavor. [Embodiment] The present invention will be hereinafter Referring to the examples for a more detailed description, Not limited to-13-201233673. Examples 1 to 3 Using a high shear granulator (device name: FM-VG-10, manufactured by Powrex Corporation), using pure water as a solvent, according to the formulation ratio in Table 1, Form C crystal of 4-(3·chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as Compound A), D-mannitol (trade name: Mannitol 'Merck), precipitated calcium carbonate (trade name: Whiton F, Shiraishi Calcium), propyl cellulose (HPC-L, Nippon Soda), low substitution Hydroxypropyl cellulose (trade name: L-HPC (LH-21), Shin-Etsu Chemical), and microcrystalline cellulose (trade name: Ceolus PH-101, Asahi Kasei Chemicals) were subjected to wet granulation. The water content of the granules was reduced to less than 2% by additional drying, and the granules were sieved using a screening mill (device name: Power Mill P-04S, manufactured by Showa Giken KK) to make the particle diameter smaller than 1 mm. Then, microcrystalline cellulose (trade name: Ceolus PH-102 'Asahi Kasei Chemicals) and talc (trade name: Hi-Filler 17, Iwai Chemicals Company) were added to the sieved particles according to the formulation ratio in Table 1. The mixture was thoroughly mixed using a diffusion (rolling type) mixer (trade name: 10L/20L Exchange-type Tumbler Mixer, manufactured by Toyo Packing Corporation). 100 mg of the obtained granules were filled in a hard capsule of size #4 to prepare a capsule containing Compound A. -14- 201233673 [Table 1] Example 1 Example 2 Example 3 Compound A 1.25 5 12.5 Precipitated calcium carbonate 33 33 33 D-mannitol 19.75 16 8.5 Hydroxypropyl cellulose 3 3 3 Low-substituted hydroxypropyl cellulose 25 25 25 Microcrystalline cellulose (PH-101) 10 10 10 Microcrystalline cellulose (PH-102) 5 5 5 Talc 3 3 3 All 100 100 100 Unit: % by weight Examples 4 to 9 and Comparative Examples 1 to 2化合物 and 杵, Compound A, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, D_mannitol, and talc were thoroughly mixed according to the formulation ratios in Tables 2 and 3. 100 ml of the resulting mixture was filled in a hard capsule of size #3 to prepare capsules of Examples 4 to 9. The capsules of Comparative Examples 1 to 2 were also prepared by the same method, but they did not contain precipitated calcium carbonate. [Table 2] Comparative Example 1 Example 4 Example 5 Example 6 Compound A 5 5 5 5 Precipitated calcium carbonate 0 5 10 20 Low-substituted hydroxypropyl cellulose 30 25 20 10 D-mannitol 62 62 62 62 Talc 3 3 3 3 All 100 100 100 100 Unit: Weight % -15- 201233673 [Table 3] Comparative Example 2 Example 7 Example 8 Example 9 Compound A 20 20 20 20 Precipitated calcium carbonate 0 5 10 20 Low-substituted hydroxypropyl fiber 30 25 20 10 D-mannitol 47 47 47 47 . Talc 3 3 3 3 All 100 100 100 100 Unit weight % Test Example 1 The solubility in the capsules of Examples 4 to 9 and Comparative Examples 1 to 2 was in accordance with The dissolution test (the Paddle method, measuring JP1 solution) described in Japanese Pharmacopoeia Edition was examined. As a result, the dissolution of Compound A in the capsule in which the ratio of calcium carbonate was not mixed was insufficient. The compound A in the capsules of Examples 4 to 9 of the mixed calcium carbonate was good (Fig. 1 and Fig. 2). Example 1 〇 to 15 and Comparative Examples 3 to 4 Using hydrazine and hydrazine, according to Table 4 and Table 5, the preparation of the complex A, magnesium carbonate (Kyowa Chemical Industry), hydroxypropyl cellulose, D-mannose The alcohol and talc are thoroughly mixed. The resulting hard capsule was filled with 100 mg of the resulting mixture to make a capsule of < Comparative Example 3 to was also prepared by the same method, but it did not contain magnesium carbonate. Compound A Fifteenth test medium: Compared with the case of Example 1 to the reverse, in the dissolution example, the low substitution in the size #3 Tang Example 1〇4 of Jiaoling-16-201233673 [Table 4] Comparative Example 3 Example 10 Example 11 Example 12 Compound A 5 5 5 5 Magnesium carbonate 0 5 10 20 Low-substituted hydroxypropyl cellulose 30 25 20 10 D-mannitol "~~ 62 62 62 62 Talc 3 3 3 3 All 100 r 100 Γ 100 100 Unit: % by weight [Table 5] Comparative Example 4 Example 13 Example 14 Example 15 Compound A 20 20 20 20 Carbonic acid Table 0 5 10 20 Low-substituted indole fiber table 30 25 20 10 D-mannitol 47 4*7 47 47 Talc 3 3 3 3 100 100 100 100 Unit··% by weight Test Example 2 The dissolution of Compound A in the capsules of Examples 1 to 15 and Comparative Examples 3 to 4 was carried out in the same manner as in Test Example 1. test. The dissolution of Compound A in the capsules of Comparative Examples 3 to 4 in which magnesium carbonate was not mixed was insufficient. Conversely, the dissolution of Compound A in the capsules of Examples 10 to 15 in which calcium carbonate was mixed was good (Fig. 3 and Fig. 4). Examples 16 to 17 and Comparative Examples 5 to 6 used ruthenium and osmium, Pure water is added to Compound A, precipitated calcium carbonate or magnesium carbonate, hydroxypropyl cellulose, and croscarmellose sodium (trade name: Ac-Di-Sol, Asahi Kasei Chemicals) for granulation, followed by granulation. The dried granules are screened to have a particle diameter of less than 1 mm. Then, according to the formulation ratio in Table 6 according to -17-201233673, microcrystalline hydroxypropyl cellulose (trade name: Ceolus PH-102 · Asahi Kasei Chemicals), low-substituted propyl cellulose and talc (trademark The name: Hi-Filler 17, Iwai Chemicals Company) was added to the screened granules and the mixture was thoroughly mixed. 100 mg of the resulting mixture was filled in a hard capsule of size #4 to prepare capsules of Examples 16 to 17. The capsules of Comparative Examples 5 to 6 were also prepared in the same manner as in the formulation ratios in Table 7, except that they contained neither precipitated calcium carbonate nor magnesium carbonate, but contained mannitol or talc as a substitute. [Table 6] Example 16 Example 17 Compound A 10 10 Precipitated calcium carbonate 15 0 Magnesium carbonate 0 15 Hydroxypropyl cellulose 2 2 Crosslinked hydroxymethyl ether cellulose sodium 10 10 Low-substituted hydroxypropyl cellulose 20 20 μ Crystalline cellulose (PH-102) 41 41 Talc 2 2 All 100 100 Units % by weight [Table 7] Comparative Example 5 Comparative Example 6 Compound A 10 10 Mannitol 15 0 Talc 0 15 Hydroxypropylcellulose 2 2 Sodium hydroxymethyl ether cellulose 10 10 Low-substituted hydroxypropyl cellulose 20 20 Microcrystalline cellulose (PH-102) 41 41 Talc 2 2 All 100 100 Unit weight % -18- 201233673 Test Example 3 In Example 16 The dissolution of Compound a in the capsules of 17 and Comparative Example 5 was examined in the same manner as in Test Example i. The dissolution of Compound A in the capsule of Comparative Example 5 in which neither calcium carbonate nor magnesium carbonate was mixed was insufficient. In contrast, the dissolution of Compound a in the capsules of Examples 16 to 17 in which calcium carbonate or magnesium carbonate was mixed was good (Fig. 5). Test Example 4 The capsules of Examples 16 to 17 and Comparative Example 6 were placed at a temperature of 60. (: The temperature and the relative humidity of 75 % were stored in the open system for a week, then the high-performance liquid chromatography was used to determine the production of the degradant. The comparative example was neither mixed with calcium carbonate nor mixed with magnesium carbonate. In the capsule blend of 6, the amount of the degradant was increased. Conversely, in the capsules of Examples 16 to 17 in which calcium carbonate or magnesium carbonate was mixed, no increase in degradation products was observed (Table 8). [Table 8] Degradant (%) Quantitative Compound A (%) Compound A (initial) 1.61% 98.38% Comparative Example 6 1.92% 98.08% _Example 16 1.50% 98.50% » Example 17 1.57% 98.44% Example 1 8 to 19 and Comparative Example 7 By the same method as in Examples 4 to 9 and Comparative Examples 1 to 2, the individual components were mixed according to the blending ratio of Tables 9 and 10. The hard capsule of size #3 was filled with 1 mg of the powder. The resulting mixture was prepared as capsules of Examples 18 to 19 and Comparative Examples 7 to 1 。. -19-201233673 [Table 9] Example 18 Comparative Example 7 Comparative Example 8 Compound A 20 20 20 ^Methyl carbonate 10 0 0 Calcium oxide 0 10 0 Calcium hydroxide 0 0 10 Low substituted hydroxypropyl cellulose 20 20 20 D-mannitol 47 47 47 Talc 3 3 3 All 100 100 100 Unit: % by weight [Table 10] Example 19 Comparative Example 9 Comparative Example 10 Sigma A 20 20 20 Magnesium Carbonate 10 0 0 Magnesium Oxide 0 10 0 Magnesium Hydroxide 0 0 10 Low-substituted hydroxypropylcellulose 20 20 20 D-mannitol 47 47 47 Talc 3 3 3 All 100 100 100 Unit: % by weight Test Example 5 Compounds in the capsules of Examples 18 to 19 and Comparative Examples 7 to 1 The dissolution of a was examined by the same method as Test Example 1. As a result, the dissolution of Compound A in the capsules of Comparative Examples 7 to 10 in which Mixed Oxidation #5, Hydroxide Hydroxide, Magnesium Oxide or Magnesium Hydroxide was Mixed was Insufficient Conversely, the dissolution of Compound A in the capsules of Examples 18 to 19 in which carbonic acid consumption or magnesium carbonate was mixed was good (Fig. 6 and Fig. 7). Industrial Applicability According to the pharmaceutical composition of the present invention It is excellent in stability in the dissolution of quinoline derivatives and -20-201233673, and thus can be used as a drug for preventing or treating tumors. [Schematic Description] Fig. 1 shows examples 4 to 6 and comparative examples. The composition obtained in 1 is dissolved The change curve of Compound A. Fig. 2 shows the change curve of the composition obtained by the examples 7 to 9 and Comparative Example 2 to dissolve the compound A. Fig. 3 shows the composition obtained from the examples 丨〇 to 12 and the comparative example 3. The material dissolves the pattern of Compound A. Fig. 4 shows a graph showing the dissolution of the compound A obtained by the examples 丨3 to 15 and the composition obtained in Comparative Example 4. Fig. 5 is a graph showing the change in the dissolution of the compound A obtained from the compositions obtained in Examples 16 to 17 and Comparative Example 5. Fig. 6 shows a change curve of the compound A obtained by the dissolution of the composition obtained in Example 18 and Comparative Examples 7 to 8. Fig. 7 shows a curve in which the composition obtained in Example 19 and Comparative Examples 9 to 10 was dissolved to give a compound A. -twenty one ·