200528096 九、發明說明： 【發明所屬之技術領域】 本發明爲有關含有吲哚啉化合物之安定化醫藥組成物。 醯基-輔酶A :膽固醇醯基轉移酶抑制劑（以下稱「AC AT 抑制劑」）因抑制在小腸之膽固醇之吸收及往動脈壁之膽 固醇之蓄積，故期待成高血壓症及動脈硬化症等之有效藥 劑。尤其粥樣性動脈硬化症成爲心肌梗塞及腦梗塞、腦溢 血等之主因，故要求有效預防法及治療法。 如此AC AT抑制劑已知例如專利文獻1及專利文獻2記載 之吲哚啉衍生物。但此等吲哚啉衍生物因有安定性問題， 故難供爲分解物少而保存安定性優異之製劑。且在上述專 利文獻記載之醫藥組成物，對保存安定性等之改善手段等 無任何記載。 【專利文獻1】專利2968050號 【專利文獻2】特開平2002- 145774號 【先前技術】 [發明欲解決之課題] 本發明者等對含有N - ( 1-辛基-5·羧甲基-4，6-二甲基吲 哚啉-7-基）-2，2-二甲基丙醯胺或其藥理容許鹽之醫藥組 成物之安定性致力硏究之結果，發現於N - ( 1-辛基-5-羧甲 基-4，6-二甲基吲哚啉-7-基）-2，2-二甲基丙醯胺或其藥 理容許鹽配合當作安定劑之抗氧化劑，酸性化合物或彼等 之混合物之醫藥組成物具有優異之保存及操作安定性（尤 其保存安定性），可當作溫血動物用（尤其人用）之醫藥 2Ό0528096 · . 品製劑，終於完成本發明。 【發明內容】 [解決課題之手段] 本發明爲： (1 ) 含有N - ( 1-辛基-5-羧甲基-4，6-二甲基吲哚琳-7-基 )-2，2-二甲基丙醯胺或其藥理容許鹽，及當作安定 劑之藥理容許之抗氧化劑之醫藥組成物。 (2 ) 含有N - ( 1-辛基-5-羧甲基-4，6-二甲基吲哚啉-7-基 9 ) -2，2-二甲基丙醯胺或其藥理容許鹽，及當作安定 劑之藥理容許之酸性化合物之醫藥組成物。 (3) 含有N-(l-辛基-5-羧甲基-4，6-二甲基吲哚啉-7-基 )-2，2-二甲基丙醯胺或其藥理容許鹽，及當作安定 劑之藥理容許之抗氧化劑及藥理容許之酸性化合物之 醫藥組成物。 本發明宜（1 )或（3 )之醫藥品組成物中， (4 )抗氧化劑爲亞硫酸氫鈉，亞硫酸鈉，焦亞硫酸鈉， ^ 乙二胺四乙酸鈣二鈉，乙二胺四乙酸鈉，乙二胺四乙 酸四鈉，抗壞血酸，抗壞血酸鈉，抗壞血酸鈣，抗壞 血酸硬脂酸酯，抗壞血酸十六酸酯，異抗壞血酸，異 抗壞血酸鈉，天然維生素E，生育酚，δ-生育酚， 乙酸α-生育酚，丁二酸α-生育酚，丁二酸α-生育酚鈣 ，二丁羥基甲苯，丁羥基甲氧苯，没食子酸丙酯或此 等之混合物之醫藥品組成物。 (5 )抗氧化劑爲抗壞血酸，抗壞血酸鈉，α -生育酚，乙 200528096 - 酸α-生育酚，丁二酸α-生育酚鈣或此等之混合物之醫 藥組成物。 (6 )抗氧化劑爲抗壞血酸，抗壞血酸鈉或此等之混合物 之醫藥組成物，又於（2 )或（3 )之醫藥組成物， (7 )酸性化合物爲有機酸之醫藥組成物。 (8)酸性化合物爲甲磺酸，三氟甲磺酸，乙磺酸，苯磺 酸，對甲苯磺酸，乙酸，草酸，蘋果酸，富馬酸，馬 來酸，丁二酸，檸檬酸，酒石酸，抗壞血酸，甘胺酸 • ，離胺酸，精胺酸，鳥胺酸，麩胺酸，天冬胺酸或此 等之混合物，尤宜乙酸，草酸，蘋果酸，富馬酸，馬 來酸，丁二酸，檸檬酸，酒石酸，抗壞血酸或此等之 混合物之醫藥混合物。 (9 )酸性化合物爲乙酸，草酸，蘋果酸，富馬酸，馬來 酸，丁二酸，檸檬酸，酒石酸，抗壞血酸或此等之混 合物之醫藥組成物。 (10) 酸性化合物爲富馬酸，馬來酸，丁二酸，檸檬酸， ® 酒石酸或此等之混合物之醫藥品組成物。 (11) 酸性化合物爲酒石酸之醫藥組成物，且 更於（3 )之醫藥組成物中， (12) 抗氧化劑爲抗壞血酸，抗壞血酸鈉或此等之混合物 ，酸性化合物爲酒石酸之醫藥組成物。 本發明更於前述（1 )乃至（1 2 )之醫藥組成物中， (1 3 ) 動脈硬化症之預防或治療之醫藥組成物 (1 4 ) 起因於動脈硬化之疾病之預防或治療之醫藥組成物 200528096 更於（1 4)之醫藥組成物中， (15) 起因於動脈硬化之疾病爲絶血性心疾病之醫藥組成 物 (16) 起因於動脈硬化之疾病爲絶血性腦疾病之醫藥組成 物 (17) 起因於動脈硬化之疾病爲末梢循環不全症之醫藥組 成物。 φ 本發明之醫藥組成物之有效成分N-(l-辛基-5-羧甲基-4 ，6-二甲基吲哚啉-7-基）-2，2-二甲基丙醯胺爲前述專利 文獻1之實施例4記載之具有下述構造式之化合物。200528096 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a stabilized pharmaceutical composition containing an indololine compound. Amylyl-Coenzyme A: Cholesterol amylyltransferase inhibitor (hereinafter referred to as "AC AT inhibitor") inhibits the absorption of cholesterol in the small intestine and the accumulation of cholesterol to the arterial wall, so it is expected to become hypertension and arteriosclerosis Wait for effective potions. In particular, atherosclerotic arteriosclerosis has become the main cause of myocardial infarction, cerebral infarction, and cerebral hemorrhage. Therefore, effective prevention and treatment are required. Such AC AT inhibitors are known, for example, from indolinoline derivatives described in Patent Documents 1 and 2. However, these indolinoline derivatives are difficult to provide as a preparation having few decomposition products and excellent storage stability due to stability problems. In addition, the pharmaceutical composition described in the above patent documents does not include any improvement measures such as preservation stability. [Patent Document 1] Patent No. 2968050 [Patent Document 2] Japanese Patent Application Laid-Open No. 2002-145774 [Prior Art] [Problems to be Solved by the Invention] The present inventors et al. 4,6-Dimethylindolin-7-yl) -2,2-dimethylpropanamine or a pharmacologically acceptable salt of the pharmaceutical composition of the result of intensive research, found in N-(1 -Octyl-5-carboxymethyl-4,6-dimethylindololin-7-yl) -2,2-dimethylpropanamide or a pharmacologically acceptable salt thereof as an antioxidant, The pharmaceutical composition of acidic compounds or their mixtures has excellent storage and handling stability (especially storage stability), and can be used as a medicine for warm-blooded animals (especially for human use) 2Ό0528096.. The product has finally completed the present invention . [Summary of the Invention] [Means for Solving the Problems] The present invention is: (1) containing N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2, 2-dimethylpropanamide or a pharmacologically acceptable salt thereof, and a pharmaceutical composition of a pharmacologically acceptable antioxidant as a stabilizer. (2) Containing N-(1-octyl-5-carboxymethyl-4,6-dimethylindololin-7-yl 9) -2,2-dimethylpropanamide or a pharmacologically acceptable salt thereof And pharmaceutical compositions of acidic compounds that are pharmacologically acceptable as stabilizers. (3) Containing N- (l-octyl-5-carboxymethyl-4,6-dimethylindololin-7-yl) -2,2-dimethylpropanamide or a pharmacologically acceptable salt thereof, And as a stabilizer, pharmacologically acceptable antioxidants and pharmacologically acceptable acidic compounds. In the pharmaceutical composition of (1) or (3) of the present invention, (4) the antioxidant is sodium bisulfite, sodium sulfite, sodium metabisulfite, ^ calcium ethylenediamine tetraacetate disodium, sodium ethylenediamine tetraacetate, Tetrasodium ethylenediamine tetraacetate, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbyl stearate, ascorbyl hexadecanoate, erythorbic acid, sodium erythorbate, natural vitamin E, tocopherol, δ-tocopherol, α-acetate Pharmaceutical composition of tocopherol, α-tocopheryl succinate, calcium α-tocopheryl succinate, dibutylhydroxytoluene, butoxymethoxybenzene, propyl gallate or mixtures thereof. (5) Antioxidant is a medicinal composition of ascorbic acid, sodium ascorbate, α-tocopherol, ethyl 200528096-acid α-tocopherol, calcium succinate α-tocopherol calcium or a mixture thereof. (6) The antioxidant is a pharmaceutical composition of ascorbic acid, sodium ascorbate or a mixture thereof, and the pharmaceutical composition of (2) or (3), (7) the acidic compound is a pharmaceutical composition of organic acid. (8) Acidic compounds are methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, oxalic acid, malic acid, fumaric acid, maleic acid, succinic acid, and citric acid. , Tartaric acid, ascorbic acid, glycine •, lysine, arginine, ornithine, glutamic acid, aspartic acid or mixtures thereof, especially acetic acid, oxalic acid, malic acid, fumaric acid, horse Pharmacological mixture of maleic acid, succinic acid, citric acid, tartaric acid, ascorbic acid or a mixture of these. (9) The acidic compound is a pharmaceutical composition of acetic acid, oxalic acid, malic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, ascorbic acid or a mixture of these. (10) Acidic compounds are pharmaceutical compositions of fumaric acid, maleic acid, succinic acid, citric acid, ® tartaric acid or mixtures thereof. (11) The acidic compound is a pharmaceutical composition of tartaric acid, and more than the pharmaceutical composition of (3), (12) The antioxidant is ascorbic acid, sodium ascorbate or a mixture thereof, and the acidic compound is a pharmaceutical composition of tartaric acid. The present invention further relates to the aforementioned (1) to (1 2) pharmaceutical composition, (1 3) a pharmaceutical composition for preventing or treating arteriosclerosis (1 4) a medicine for preventing or treating arteriosclerotic diseases Composition 200528096 More than (1 4) of the medical composition, (15) The medical composition of the disease caused by arteriosclerosis is a hemostatic heart disease (16) The medical composition of the disease caused by arteriosclerosis is a hemostatic brain disease (17) A disease caused by arteriosclerosis is a medicinal composition of peripheral circulation insufficiency. φ N- (l-octyl-5-carboxymethyl-4,6-dimethylindololine-7-yl) -2,2-dimethylpropanamide, the active ingredient of the pharmaceutical composition of the present invention The compound described in Example 4 of the aforementioned Patent Document 1 has the following structural formula.
本發明之醫藥組成物之有效成分N - ( 1-辛基-5-羧甲基-4 ，6-二甲基吲哚啉-7-基）-2，2-二甲基丙醯胺必要時可依 常法作成鹽。例如於溶劑中（可爲例如醚類、酯類或醇類 ，宜醚類），與相當酸於室溫處理5分乃至3 0分，濾取析 出之結晶或減壓蒸除溶劑而得。如此鹽可爲氫氟酸鹽、鹽 酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、過氯酸鹽、硫酸鹽 或磷酸鹽等礦酸鹽；甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽 200528096 、苯磺酸鹽或對甲苯磺酸鹽等磺酸鹽；富馬酸鹽、丁二酸 鹽、檸檬酸鹽、酒石酸鹽、草酸鹽或馬來酸鹽等羧酸鹽； 或麩胺酸鹽或天冬胺酸鹽等胺基酸鹽。 本發明之醫藥組成物之有效成分N - ( 1-辛基-5-羧甲基-4 ，6-二甲基吲哚啉-7-基）-2，2-二甲基丙醯胺或其藥理容 許鹽可以水合物存在，如此水合物也包含於本發明。 本發明醫藥組成物之安定劑之抗氧化劑可爲例如亞硫酸氫 鈉、亞硫酸鈉、焦亞硫酸鈉、乙二胺四乙酸鈣二鈉、乙二 胺四乙酸鈉、乙二胺四乙酸四鈉、抗壞血酸、抗壞血酸鈉 、抗壞血酸鈣、抗壞血酸硬脂酸酯、抗壞血酸十六酸酯、 異抗壞血酸、異抗壞血酸鈉、天然維生素E、α-生育酚、 δ-生育酚、乙酸α-生育酚、丁二酸α-生育酚、丁二酸α-生 育酚鈣、二丁羥基甲苯、丁羥基甲氧苯、没食子酸丙酯或 此等之混合物，宜抗壞血酸、抗壞血酸鈉、α-生育酚、乙 酸α-生育酚、丁二酸α-生育酚鈣或此等之混合物、尤宜抗 壞血酸、抗壞血酸鈉或此等之混合物。 本發明醫藥組成物之安定劑之酸性化合物可爲無機酸乃至 有機酸，又可水溶性乃至幾不溶解於水或本質上不溶解於 水之範圍內之物質，只要爲通常之藥理容許之酸性化合物 ，則無特限，宜有機酸。如此有機酸可爲例如氫氟酸、鹽 酸、氫溴酸、氫碘酸等氫鹵酸；硝酸；過氯酸；硫酸；磷 酸；亞磷酸；碳酸；甲磺酸、三氟甲磺酸、乙磺酸、五氟 乙磺酸、丙磺酸等可有氟基取代之C ! - C 6烷基磺酸；苯磺 酸、對甲苯磺酸、2，4-二甲基苯磺酸、2，4，6-三甲基苯 200528096 . - 擴酸、4 -乙基苯擴酸、1 -萘磺酸、2 -萘擴酸等C 6 - C 1 q芳基 磺酸；乙酸、草酸、蘋果酸、三氟乙酸、丙酸、丁酸、丙 二酸、富馬酸、馬來酸、丁二酸、檸檬酸、酒石酸等飽和 或不飽和C ! - C , 〇脂肪族羧酸；抗壞血酸；苯甲酸、酞酸 等c 7- C 12芳香族羧酸；或甘胺酸、離胺酸、精胺酸、鳥 胺酸、麩胺酸、天冬胺酸等胺基酸、宜乙酸、草酸、蘋果 酸、富馬酸、馬來酸、丁二酸、檸檬酸、酒石酸、抗壞血 酸或此等之混合物，更宜富馬酸、馬來酸、丁二酸、檸檬 ® 酸、酒石酸或此等之混合物，尤宜酒石酸。 當作本發明之安定劑使用之抗氧化劑通常爲0.1至5重量 份，宜0 · 5至2.5重量份。 當作本發明之安定劑使用之酸性化合物通常爲0.1至1 0 重量份，宜0.5至5重量份。 本發明之醫藥品組成物可以錠劑、膠囊劑、九劑、顆粒劑 或細粒等可經口投與可能之製劑使用，宜錠劑。 本發明之醫藥組成物可適宜地含有製藥容許之添加物。 Φ 如此添加物可爲例如賦形劑（例如乳糖、白糖、葡萄糖、 甘露糖醇、山梨糖醇等糖衍生物；玉米澱粉、馬鈴薯澱粉 、α化澱粉、糊精、羧甲基澱粉、羧甲基澱粉鈉等澱粉衍 生物；預先明膠化之澱粉；結晶纖維素、甲基纖維素、羥 丙基纖維素、低取代度羥丙基纖維素、羥丙基甲基纖維素 、羧甲基纖維素、羧甲基纖維素鈣、內部交聯羧甲基纖維 素、內部交聯羧甲基纖維素鈉等纖維素衍生物；阿拉伯膠 •’聚葡萄糖；聚三葡萄糖；輕質矽酸酐、矽酸鈣、矽酸水 -10- 200528096 合物、合成矽酸鋁、偏矽酸鋁酸鎂等 二鈣等磷酸鹽衍生物；氯化鈉等氯化 碳酸鹽衍生物；硫酸鈣等硫酸鹽衍生 ，宜糖衍生物、纖維素衍生物或此等 、甘露糖醇、結晶纖維素或此等之混 如於上述賦形劑例示之化合物；明膠 聚乙二醇；或此等之混合物，宜纖維 合物，更宜羥丙基甲基纖維素）、崩 形劑例示之化合物；交聯聚乙烯吡咯 物，宜纖維素衍生物或此等之混合物 基纖維素、交聯聚乙烯吡咯啶酮或此 劑（例如硬脂酸；硬脂酸鈣、硬脂酸 苯甲酸鈉等苯甲酸金屬鹽；蜂膠、鯨 二醇；富馬酸、己二酸等羧酸類；硫 白胺酸；十二基硫酸鈉、十二基硫酸 鹽；於上述賦形劑例示之矽酸鹽衍生 示之澱粉衍生物；氫化植物油；棕櫚 或此等之混合物，宜硬脂酸金屬鹽、 之混合物，更宜硬脂酸鈣、硬脂酸鎂 混合物）、安定劑（例如苯甲酸；苯 鹽；對羥苯甲酸甲酯、對羥苯甲酸丙 ;氯丁醇、苄醇、苯乙醇等醇類；苄 等酚類；硫柳汞；乙酸酐；山梨酸； 苯甲酸金屬鹽、對羥苯甲酸酯類或此 矽酸鹽衍生物；磷酸 鹽衍生物；碳酸鈣等 物；或此等之混合物 之混合物，更宜乳糖 合物）、結合劑（例 :聚乙烯吡咯啶酮； 素衍生物或此等之混 壊劑（例如於上述賦 啶酮；或此等之混合 ，更宜低取代度羥丙 等之混合物）、滑澤 鎂等硬脂酸金屬鹽； 蠟等蠟類；硼酸；乙 酸鈉等硫酸金屬鹽； 鎂等十二基硫酸金屬 物；於上述賦形劑例 鱲；蔗糖脂肪酸酯； 矽酸鹽衍生物或此等 、無水矽酸或此等之 甲酸鈉等苯甲酸金屬 酯等對羥苯甲酸酯類 烷氯化銨；酚、甲酚 或此等之混合物，宜 等之混合物，更宜苯 -11 - 200528096 甲酸鈉、對羥苯甲酸甲酯、對羥苯甲酸丙酯或此等之混合 物）、流動化劑（例如於上述賦形劑例示之矽酸鹽衍生物 ;滑石；或此等之混合物，宜輕質矽酸酐、滑石或此等之 混合物）、界面活性劑（例如聚山梨酸酯8 〇等聚山梨酸酯 類；聚氧乙烯硬化蓖麻油6 0等聚氧乙烯硬化蓖麻油類；山 梨酸酯脂肪酸酯類；蔗糖脂肪酸酯類；聚氧乙烯聚氧丙烯 乙二醇類；聚氧乙烯脂肪酸醚類；硬脂酸聚氧酯類；或此 等之混合物’宜聚山梨酸酯80、聚氧乙烯硬化蓖麻油60 或此等之混合物）、著色劑、抗氧化劑、矯味矯臭劑（例 如通常使用之甘味料、酸味料、香料等）或稀釋劑，使用 之添加劑之種類及量依錠劑、膠囊劑或其他之投與形態藥 劑而異，可由製劑領域之周知之技術來選擇。 例如爲錠劑時，全藥劑組成物中結合劑之含量通常爲1至 1〇重量份（宜2至5重量份），崩壊劑之含量通常爲1至 4〇重量份（宜5至30重量份），滑澤劑之含量通常爲0.1 至1 〇重量份（宜〇· 5至3重量份），流動化劑之含量爲1 至10重量份（宜2至5重量份）。 本發明之醫藥組成物可用藥理容許之添加物依周知之方法 (例如用水揑合之方法、濕式粒狀化方法等）容易製造。 如此製造之例可例如添加有效成分、安定劑、賦形劑、結 合劑、崩壊劑及必要時其他種類之助劑等，用高速攪拌造 粒機混合，於所得混合物以流動層造粒機噴霧結合劑之水 溶液，所得造粒物用流動層乾燥器乾燥，乾燥之造粒物用 破碎造粒整粒機強制通過篩，加滑澤劑、崩壊劑及必要時 -12- 200528096 -其他種類之助劑等而以V型混合機混合，所得混合物予以 打錠或裝入膠囊，可分別製造錠劑或膠囊劑。 所得錠劑必要時施加糖衣或被覆（宜被覆）。例如於所得 錠劑將由羥丙基甲基纖維素、滑石、氧化鈦、乳糖、三乙 酸甘油酯或聚乙烯乙二醇、黄色三氧化二鐵或三氧化二鐵 及水而成之被覆液於盤被覆機中噴霧來施加薄膜被覆。 又由上述之高速攪拌造粒機混合，將加結合劑之水溶液而 揑合所得之揑合物以擠壓造粒機作成顆粒後，由栅式乾燥 • 機乾燥，將乾燥之顆粒物以破碎造粒整粒機，強制通過篩 ，則得顆粒劑。 本發明之醫藥組成物可投與溫血動物（尤其人），有效成 分N-(l -辛基-5-羧甲基-4，6 -二甲基吲哚啉-7-基）-2，2-二甲基丙醯胺或其藥理容許鹽之投與量乃依患者之症狀、 年齢、體重等之種種條件而變化，例如經口投與時，對成 人每回 〇.lmg/Kg 〜20mg/Kg (宜 0.5mg/Kg 〜5mg/Kg)，依 症狀每日投與1至6回。 B [發明之效果] 依本發明可提供N - ( 1-辛基-5-羧甲基-4，6-二甲基吲哚 啉-7-基）-2，2-二甲基丙醯胺或其藥理容許鹽之安定化醫 藥組成物。 【實施方式】 次舉實施例更詳細説明本發明，本發明不限於此。試驗化 合驗使用N-([辛基-5-羧甲基-4，6-二甲基吲哚啉-7-基 )-2，2-二甲基丙醯胺之半硫酸鹽。 -13 - 200528096 [實施例1]錠劑 用表1所示種類及量之成分，依以下方法製造含有試驗 化合物之錠劑1、錠劑2及錠劑3。 在試驗化合物添加賦形劑（乳糖）、崩壊劑（交聯聚乙 烯吡咯啶酮）、抗氧化劑或酸性化合物或彼等之混合物， 以高速攪拌造粒機混合，在所得混合物以流動層造粒機噴 霧結合劑（羥丙基纖維素）水溶液。所得造粒物以流動層 乾燥機乾燥，將乾燥之造粒物以破碎造粒整粒機強制通過 篩，加崩壊劑（低取代度羥丙基甲基纖維素）、成型助劑 (矽酸鈣）、滑澤劑（硬脂酸鎂）而以V型混合機混合。 所得混合物以直徑9 · 5 m m之杵成形，得所望之錠劑。 (表1) 成分 (§€劑編號) 每錠之量（mg) 1 2 3 試驗化合物 27.94 27.94 27.94 乳糖 220.31 210.81 207.81 交聯聚乙烯吡咯啶酮 20 20 20 羥丙基纖維素 7.5 7.5 7.5 抗壞血酸 3 - 3 酒石酸 - 12.5 12.5 低取代度羥丙基纖維素 62.5 62.5 62.5 矽酸鈣 7.5 7.5 7.5 硬脂酸鎂 11.25 11.25 11.25 合計 360 360 360 (參考例1 )比較對照用錠劑 用表2所示種類及量之成分，依如下方法製造含有試驗 化合物之比較對照用之錠劑4。 •14- 200528096 . .在試驗化合物加賦形劑（乳糖）、崩壊劑（交聯聚乙烯吡咯 啶酮），以高速攪拌造粒機混合，所得之混合物由流動層造 粒機嘖霧結合劑（羥丙基纖維素）水溶液。所得造粒物以流動 層乾燥機乾燥，所乾燥之造粒物以破碎造粒整粒機強制通過 篩，加崩壊劑（低取代度羥丙基甲基纖維素）、成型助劑（矽 酸鈣）、滑澤劑（硬脂酸鎂）而以V型混合機混合。所得混合物 以直徑9.5mm之杵成形，得所望之錠劑。 (表2) 成分 每錠之量（mg) (錠劑編號） 4 (比較對照用） 試驗化合物 27.94 乳糖 223.31 交聯聚乙烯吡咯啶酮 20 羥丙基纖維素 7.5 抗壞血酸 • 酒石酸 細 低取代度羥丙基纖維素 62.5 矽酸鈣 7.5 硬脂酸鎂 11.25 合計 360 (試驗例1 )安定性試驗 將實施例所得之試驗錠劑及參考例所得之比較對照用之 錠劑投入褐色玻璃瓶，以密閉狀態在40°C /75% R Η静置 ，經過6個月後之錠劑中之不純物以高速液體層析測定。 高速液體層析之測定條件如下。 柱：The N- (1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropanamide is an effective ingredient of the pharmaceutical composition of the present invention It can be made into salt according to the usual method. For example, in a solvent (for example, ethers, esters, or alcohols, preferably ethers), treated with a fairly acid at room temperature for 5 minutes to 30 minutes, and filtering the precipitated crystals or distilling off the solvent under reduced pressure. Such salts may be mineral salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodate, nitrate, perchlorate, sulfate or phosphate; mesylate, trifluoromethanesulfonate Acid salt, ethanesulfonate 200528096, benzenesulfonate or p-toluenesulfonate, etc .; fumarate, succinate, citrate, tartrate, oxalate or maleate, etc. Carboxylic acid salts; or amino acid salts such as glutamate or aspartate. The active ingredient of the pharmaceutical composition of the present invention is N-(1-octyl-5-carboxymethyl-4,6-dimethylindololin-7-yl) -2,2-dimethylpropanamide or The pharmacologically acceptable salt thereof may exist as a hydrate, and thus the hydrate is also included in the present invention. The antioxidant of the stabilizer of the pharmaceutical composition of the present invention may be, for example, sodium bisulfite, sodium sulfite, sodium metabisulfite, disodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, ascorbic acid, Sodium ascorbate, calcium ascorbate, ascorbyl stearate, ascorbyl hexadecanoate, erythorbic acid, sodium erythorbate, natural vitamin E, α-tocopherol, δ-tocopherol, α-tocopheryl acetate, succinic acid α- Tocopherol, calcium succinate α-tocopherol, dibutylhydroxytoluene, butyl methoxytoluene, propyl gallate or a mixture of these, preferably ascorbic acid, sodium ascorbate, α-tocopherol, α-tocopheryl acetate, Calcium succinate α-tocopherol or a mixture thereof, particularly ascorbic acid, sodium ascorbate or a mixture thereof. The acidic compound of the stabilizer of the pharmaceutical composition of the present invention may be an inorganic acid or an organic acid, and may be water-soluble or even a substance that is insoluble in water or substantially insoluble in water, as long as it is an acid that is generally pharmacologically acceptable Compounds are not limited, and organic acids are preferred. Such organic acids may be, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, and hydroiodic acid; nitric acid; perchloric acid; sulfuric acid; phosphoric acid; phosphorous acid; carbonic acid; methanesulfonic acid, trifluoromethanesulfonic acid, ethyl Sulfonic acid, pentafluoroethanesulfonic acid, propanesulfonic acid, etc. may have fluorine-substituted C! -C 6 alkylsulfonic acid; benzenesulfonic acid, p-toluenesulfonic acid, 2,4-dimethylbenzenesulfonic acid, 2 , 4,6-trimethylbenzene 200528096.-C6-C 1 q arylsulfonic acid, such as acid, 4-ethylbenzene acid, 1-naphthalenesulfonic acid, 2-naphthalene acid; acetic acid, oxalic acid, Malic acid, trifluoroacetic acid, propionic acid, butyric acid, malonic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid and other saturated or unsaturated C! -C, O aliphatic carboxylic acids; ascorbic acid C 7-C 12 aromatic carboxylic acids such as benzoic acid and phthalic acid; or amino acids such as glycine, lysine, spermine, ornithine, glutamic acid, aspartic acid, etc., preferably acetic acid, Oxalic acid, malic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, ascorbic acid or a mixture of these, more preferably fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid or this Waiting Compound, especially tartaric acid. The antioxidant used as the stabilizer of the present invention is usually 0.1 to 5 parts by weight, preferably 0.5 to 2.5 parts by weight. The acidic compound used as the stabilizer of the present invention is usually 0.1 to 10 parts by weight, preferably 0.5 to 5 parts by weight. The pharmaceutical composition of the present invention can be used in the form of tablets, capsules, nine-dose, granules or fine granules, etc., which can be administered orally, and is suitable for tablets. The pharmaceutical composition of the present invention may suitably contain pharmaceutically acceptable additives. Φ Such additives can be, for example, excipients (such as sugar derivatives such as lactose, white sugar, glucose, mannitol, sorbitol, etc .; corn starch, potato starch, alpha starch, dextrin, carboxymethyl starch, carboxymethyl Starch derivatives such as sodium starch; pregelatinized starch; crystalline cellulose, methyl cellulose, hydroxypropyl cellulose, low-substitution hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl fiber Cellulose derivatives such as cellulose, calcium carboxymethyl cellulose, internal croscarmellose, internal croscarmellose sodium; acacia gum • polydextrose; polytriglucose; light silicic acid anhydride, silicon Calcium acid, silicic acid-10-200528096 compounds, synthetic calcium silicates such as dicalcium such as aluminum silicate and magnesium aluminosilicate; chlorinated carbonate derivatives such as sodium chloride; sulfate derivatives such as calcium sulfate , Sugar derivatives, cellulose derivatives or the like, mannitol, crystalline cellulose or the like compounds exemplified in the above excipients; gelatin polyethylene glycol; or mixtures of these, preferably fibers Compound, more preferably hydroxypropyl methyl ester Cellulose), compounds exemplified by disintegrants; cross-linked polyvinyl pyrroles, preferably cellulose derivatives or mixtures thereof, cellulose, cross-linked polyvinyl pyrrolidone or this agent (eg stearic acid; stearic acid Metal salts of benzoic acid such as calcium acid and sodium benzoate; propolis, cetyl glycol; carboxylic acids such as fumaric acid and adipic acid; thioleucine; sodium dodecyl sulfate, dodecyl sulfate; Exemplary silicate-derived starch derivatives; hydrogenated vegetable oils; palm or mixtures thereof, preferably metal stearate, mixtures thereof, more preferably calcium stearate, magnesium stearate mixture), stability Agents (such as benzoic acid; benzene salts; methyl parabens, propyl parabens; alcohols such as chlorobutanol, benzyl alcohol, phenethyl alcohol; phenols such as benzyl; thimerosal; acetic anhydride; sorbic acid; benzoic acid Metal salts, parabens or silicate derivatives; phosphate derivatives; calcium carbonate, etc .; or mixtures of these mixtures, more preferably lactose compounds), binding agents (eg, polyvinylpyrrole Pyridone; a derivative or a mixture of these (For example, in the above-mentioned aziridone; or a mixture of these, more preferably a mixture of low-substitution hydroxypropyl etc.), metal stearates such as smooth magnesium, waxes such as waxes; boric acid; metal sulfates such as sodium acetate; Metals such as magnesium dodecyl sulfate; in the above examples of excipients; sucrose fatty acid esters; silicate derivatives or metal benzoates such as anhydrous silicic acid or these sodium formate; parabens Alkane-like ammonium chloride; phenol, cresol or a mixture thereof, preferably a mixture thereof, more preferably benzene-11-200528096 sodium formate, methyl paraben, propyl paraben or the like), Fluidizers (such as the silicate derivatives exemplified in the above excipients; talc; or a mixture of these, preferably light silicic anhydride, talc or a mixture thereof), a surfactant (such as polysorbate 8 〇 Equal polysorbates; Polyoxyethylene hardened castor oil 60 0 Polyoxyethylene hardened castor oils; Sorbate fatty acid esters; Sucrose fatty acid esters; Polyoxyethylene polyoxypropylene glycols; Polyoxygen Ethylene fatty acid ethers; stearic acid Oxyesters; or mixtures of these; 'Polysorbate 80, polyoxyethylene hardened castor oil 60 or mixtures thereof], colorants, antioxidants, flavor correctors (such as commonly used sweeteners, sour agents , Flavors, etc.) or diluents, the type and amount of additives used will vary depending on lozenges, capsules, or other forms of administration, and can be selected by well-known techniques in the field of formulation. For example, in the case of a tablet, the content of the binder in the whole pharmaceutical composition is usually 1 to 10 parts by weight (preferably 2 to 5 parts by weight), and the content of the disintegrating agent is usually 1 to 40 parts by weight (preferably 5 to 30 parts by weight). The content of the lubricating agent is usually 0.1 to 10 parts by weight (preferably 0.5 to 3 parts by weight), and the content of the fluidizing agent is 1 to 10 parts by weight (preferably 2 to 5 parts by weight). The pharmaceutical composition of the present invention can be easily manufactured by pharmacologically acceptable additives in accordance with known methods (for example, a method of kneading with water, a wet granulation method, etc.). For example, the active ingredients, stabilizers, excipients, binders, disintegrating agents, and other types of auxiliaries can be added in the example produced, mixed with a high-speed agitating granulator, and the resulting mixture can be sprayed with a fluidized layer granulator. The aqueous solution of the binding agent, the obtained granulated material is dried with a flow layer dryer, and the dried granulated material is forced to pass through a sieve with a crushing granulator, and a slip agent, a disintegrating agent and, if necessary, 12- 200528096-other types of Auxiliaries and the like are mixed in a V-type mixer, and the obtained mixture is tableted or filled into capsules, and tablets or capsules can be manufactured separately. The obtained lozenges are applied with a sugar coating or coating if necessary (preferably coating). For example, in the obtained tablet, a coating solution made of hydroxypropyl methylcellulose, talc, titanium oxide, lactose, glycerol triacetate or polyethylene glycol, yellow iron oxide or iron oxide, and water is used. Spray in a disc coater to apply a film coating. The mixture is mixed by the above-mentioned high-speed stirring granulator, and the obtained kneaded material is kneaded by adding an aqueous solution of a binding agent to be granulated by an extrusion granulator, and then dried by a grid drying machine, and the dried granules are crushed and granulated. Granulator, forced through a sieve, to obtain granules. The medicinal composition of the present invention can be administered to warm-blooded animals (especially humans), and the effective ingredient is N- (l-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2. The dosage of 2-dimethylpropanamine or its pharmacologically acceptable salt varies depending on the patient's symptoms, age, body weight, and other conditions. For example, when administered orally, it is 0.1 mg / Kg per adult to 20mg / Kg (preferably 0.5mg / Kg ~ 5mg / Kg), 1 to 6 times daily according to symptoms. B [Effects of the invention] According to the present invention, N-(1-octyl-5-carboxymethyl-4,6-dimethylindolin-7-yl) -2,2-dimethylpropane is provided. An amine or a pharmacologically acceptable salt thereof stabilizes a pharmaceutical composition. [Embodiments] The following examples illustrate the present invention in more detail, but the present invention is not limited thereto. The test compound used N-([octyl-5-carboxymethyl-4,6-dimethylindololin-7-yl) -2,2-dimethylpropanamide hemisulfate. -13-200528096 [Example 1] Lozenges Using the ingredients and types shown in Table 1, tablets, 1, 2 and 3 containing test compounds were produced in the following manner. Add excipients (lactose), disintegrating agents (cross-linked polyvinylpyrrolidone), antioxidants or acidic compounds, or mixtures of these to the test compound, mix them with a high-speed stirring granulator, and granulate the resulting mixture in a flowing layer. Machine spray binder (hydroxypropyl cellulose) aqueous solution. The obtained granulated material is dried with a fluidized bed dryer, and the dried granulated material is forced through a sieve with a crushing granulator and granulator, and a disintegrating agent (low substitution degree hydroxypropyl methyl cellulose) and a forming aid (silicic acid) Calcium), smoothing agent (magnesium stearate) and V-type mixer. The obtained mixture was shaped with a pestle having a diameter of 9.5 mm, and the desired lozenge was obtained. (Table 1) Ingredient (§ € #) Amount per tablet (mg) 1 2 3 Test compound 27.94 27.94 27.94 Lactose 220.31 210.81 207.81 Cross-linked polyvinyl pyrrolidone 20 20 20 Hydroxypropyl cellulose 7.5 7.5 7.5 Ascorbic acid 3 -3 Tartaric acid-12.5 12.5 Low degree of substitution of hydroxypropyl cellulose 62.5 62.5 62.5 Calcium silicate 7.5 7.5 7.5 Magnesium stearate 11.25 11.25 11.25 Total 360 360 360 (Reference Example 1) For comparison and comparison, use the tablets shown in Table 2 The components of the same amount were used to prepare a tablet 4 for comparison and control containing a test compound as follows. • 14- 200528096.. Add the excipient (lactose) and disintegrating agent (cross-linked polyvinylpyrrolidone) to the test compound and mix with a high-speed agitating granulator. (Hydroxypropyl cellulose) aqueous solution. The obtained granulated material is dried with a fluidized bed dryer, and the dried granulated material is forced through a sieve with a crushing granulator, and a disintegrating tincture (low substitution degree hydroxypropyl methyl cellulose), a molding aid (silicic acid) are added. Calcium), smoothing agent (magnesium stearate) and V-type mixer. The obtained mixture was formed with a pestle having a diameter of 9.5 mm to obtain a desired lozenge. (Table 2) Ingredients per tablet (mg) (tablet number) 4 (for comparison) Test compound 27.94 Lactose 223.31 Cross-linked polyvinylpyrrolidone 20 Hydroxypropyl cellulose 7.5 Ascorbic acid • Fine low substitution degree of tartaric acid Propyl cellulose 62.5 Calcium silicate 7.5 Magnesium stearate 11.25 Total 360 (Test example 1) Stability test The test tablets obtained in the example and the comparative tablets used in the reference example were placed in brown glass bottles and sealed. The state is left at 40 ° C / 75% R. The impurities in the tablets after 6 months are measured by high-speed liquid chromatography. The measurement conditions of high-speed liquid chromatography are as follows. column:
Develosil ODS-MG-5(4,6mmIDx25cm，野村化學公司製造） -15- 200528096 .Develosil ODS-MG-5 (4,6mmIDx25cm, manufactured by Nomura Chemical Co.) -15-200528096.
4 柱溫度：4 0 °C 移動相A :乙腈/水混液（3 / 2 ) 移動相B :乙腈/水混液（3 /丄） 流量：毎分約lmL 梯度條件： 注入後25分以移動相a 100%來送液，其次之15分（注入 後25分〜40分）以直線梯度改變比率使移動相Β之比率由 0%成100% ’其次之30分（注入後40分〜70分）以移動相 | Β爲100%來送液。 檢出波長：220n m 由所得層析圖求出不純物由來之峰面積，來計算與試驗 化合物由來之峰面積相對之面積比。錠劑中不純物之合計 (% )如表3。 (表3) (錠劑編號） 安定性試驗開始時 不純物之合計（％) 6個月經過後 (40〇C/75%R Η ) 増加量 1 0.94 1.84 0.90 2 0.69 1.05 0.36 3 0.62 0.78 0.16 4 1.01 2.43 1.42 如表3所示，本發明之醫藥組成物，與不含有抗氧化劑及 酸性化合物之醫藥組成物比較，具有優異之保存安定性’ 故作爲醫藥品製劑有用。 -16-4 Column temperature: 40 ° C Mobile phase A: Acetonitrile / water mixed solution (3/2) Mobile phase B: Acetonitrile / water mixed solution (3 /) Flow rate: about 1mL gradient condition: 25 minutes after injection for mobile phase a 100% for liquid delivery, followed by 15 minutes (25 to 40 minutes after injection) to change the ratio of the mobile phase B from 0% to 100% with a linear gradient. 'Second 30 minutes (40 to 70 minutes after injection) ) Transfer liquid with mobile phase | Β as 100%. Detection wavelength: 220 nm. The area of the peak derived from the impurity is calculated from the obtained chromatogram, and the area ratio relative to the area of the peak derived from the test compound is calculated. The total (%) of impurities in the tablets is shown in Table 3. (Table 3) (No. of tablets) Total amount of impurities at the beginning of stability test (%) After 6 months (40 ° C / 75% R Η) 増 Addition amount 1 0.94 1.84 0.90 2 0.69 1.05 0.36 3 0.62 0.78 0.16 4 1.01 2.43 1.42 As shown in Table 3, the pharmaceutical composition of the present invention has superior storage stability compared with a pharmaceutical composition that does not contain antioxidants and acidic compounds, and is therefore useful as a pharmaceutical preparation. -16-