200819144 九、發明說明： 广【發明所屬之技術領域】 / 本發明係關於含有氨氯地平（Amlodipine)、提升光安 定性之經口固形組成物及製劑。 【先前技術】 屬於二氫11比咬系舞拮抗藥之氨氯地平（Am 1 odi pi ne)， 由於具有充分且恆定的血管擴張作用及不易造成心搏過速 之特性，所以在降壓治療方法中扮演重要角色。然而，氨 氯地平在二氫^比啶系化合物中雖屬不易為光分解之化合 物’但是曝光量多時仍會分解而降低其作為活化物質之功 能。因此，含有氨氯地平之經口固形組成物需要用以確保 對於光之安定性之技術。 已往，對於光為不安定之藥物之製劑化，已知有各種 4求樂物之安定化之方法。例如專利文獻丨中揭示在皮膜 中分散有著色劑之軟膠囊中，封入對於光為不安定之藥物 φ之硝苯地平（nifedipine)，而防止光所造成之分解或變質 的硝苯地平之軟膠囊。另外，專利文獻中揭示藉由含有 :、系色素或氧化鐵紅荨之硬膠囊，而使活化型維生素⑽ 類，定化之膠囊製劑。此等技術皆為在被覆對光為不安定 物的膠囊皮膜中含有著色劑，難以適用於錠劑、顆粒 劑、細粒劑、散劑等。 另方面，專利文獻3中揭示在二氫吡啶衍生物之錠 藉由塗布調配有氧化鐵之薄膜而成為對於光為安定化 之錠劑。然而，該技術增加塗布之步驟，所需時間及勞力 318705 5 200819144 :增加而提高生產成本。又，需要分割使用之㈣，會因為 塗^而掩沒該分割線故容易發生困擾，且分割後會露出其 刀軎彳面而無法期待其光安定化效果。再者，由於某種原因 而無法實施塗布工程之製劑亦無法應用上述技術。例如口 腔内崩解型製劑在製劑整體施加塗布時，會損及其在口腔 内之快速散解性及快速溶解性，而無法顯現其功能。另外， 雖然藉由僅塗布製劑中之原料藥物或含有原料藥物之粒 子，可保持製劑之快速散解性，但是此時在口腔中該等經 塗布之製劑之一部分不會崩解、溶解，由此點可預測甚難 服用e亥樂劑。X，專利文獻4中揭示含有氧化欽作為遮光 劑，並含有食用黃色5號、三氧化二鐵、黃色三氧化二鐵 作為著色劑之光安定性吡啶系化合物。然而，該文獻實際 所揭示之特徵係在藉由適當的賦形劑將阿雷地平 (Aranidipine)加以固體分散化之製劑上，噴霧含有著色劑 及遮光劑之塗布液，故此文獻實質上亦係揭示具有被覆^ _之製劑（麥照專利文獻4之第2頁第1攔第50行至第2攔 第4行、及第2頁第2攔第32行至第3頁第4攔第5行之 貫施例）。 不施加塗布之錠劑、顆粒劑、細粒劑、散劑等之光安 定化方法，在專利文獻5中揭示將選擇自黃色及紅色之著 色劑中1種以上之物質調配於光不安定性之脂溶性藥物而 成之提升光安定性之組成物。又，專利文獻6中，揭示添 加著色劑於含有光不安定性藥物之粉體中，經濕式造粒而 成之經口固形組成物。再者，非專利文獻i中記載添加黃 318705 6 200819144 二色二，化二鐵於硝苯地平之際，可抑制因光而產生氧化物 •之產里，及抑制主樂物含量之降低。然而，此文獻中並盔 、相關於氨氯地平之記載。 …、 專利文獻1 :日本特開昭55-22645號公報。 專利文獻2:日本特開平4-46122號公報。 專利文獻3 :日本特開2003-104888號公報。 專利文獻4 :日本特開2003-104887號公報。 _ 專利文獻5 :日本特開2〇〇〇-7583號公報。 專利文獻6 ··日本特開2000-191516號公報。 非專利文獻1:國際藥學期刊（Internati〇nal J〇urnai f Pharmaceutics) ， 1〇3 期，1994 年，69-76 頁。 【發明内容】 、 [發明擬解決之課題] 、，本lx月擬解決之課題係提供一種可簡便地防止氨氯地 平或其藥學上容許之鹽因光所致之變色及分解而成光安定 •化的經口固形組成物。 [解決課題之方法] 古Μ 一氫吼唆系化合物而t，由於氨氯地平之光安定性 回，因此在作為—般醫藥品而使用之範圍内，其含量之降 $幾乎不成問題。本發明研究者等發現氨氯地平不同於確 =地平’在未檢測出光所致含量降低之範圍下有變色之現 對2防止此等著色為其研究課題。上述非專利文獻1中 f色完全無記载’自然關於本課題亦無任何記載或暗 不。5亥文獻之課題係改善硝苯地平錠劑在400叹燭光 318705 7 200819144 (w-Candle)之光線下照射14日時會有45%產生分解物 另一方面，如下述試驗例中所示，由 叙劑產生錢物為1%左右之程度，其分解程度完全不同。 =卫氨氯地平之主要課題在防止著色，屬可知其與石肖 本地平之主要課題之含量降低係完全相異之現象。 和發明研究者等亦發現著色舉動本身，磺苯地 f平係完全相異°亦即’實際製絲劑加以確認 守，以相同方法製成之硝苯地平盘氨 罄#柊丁％ - +入 丁〃、虱虱地干之錠劑放置在 瓦先”不元全不同之著色舉動。在硝苯地 开“ =於石肖苯地平本身之色調而原本即為黃色之旋 :色=面在數小時之間就開始褪色，賴 色比另—方面，在氨氯地平之情形，其起勒為白 ^笨^平遠較為緩慢地著色成微黃色。由此可知 之夹動Γ者色反應和氨氯地平之著色反應顯示完全不同 气查从工 月本地十之先文定性之方法能否適用於 6中Λ’顯然完全無法_。料，上料利文獻5及 a確，忍有效者係四埽甲萘覼（menate计咖⑹及索 去酮（Sofalcone)，不僅不暑气查丄 ’、 之二氫。養物，所:更：::上=有相同架構 地平上之效果。 更為難以由上述文獻預測於氨氯 _ f進步’本發明研究者等亦發現如後述試驗例所 :成t氨ί地平中加以調配氧化鈦時，相反地會促進光所 分解之安定化劑用途；；！。又，周知作為抑制氧化 者有一丁基羥基甲苯、丁基羥基笨曱 318705 8 200819144 醚等抗乳化劑，此等抗氧化劑雖然可抑制因氨氯地 化所產生分解物之產量，但亦發現對 士 = 至少在氨氣地平上，光所造成之 不元全表示相同舉動。因此，調配氧化鐵於氨氣 = 抑制變色效果係完全無法預測。寸 隨著高齡化社會之演進，由於各種生理機能 ^牛低或老人性失智症等，攝取食物功能（例㈣ 寺之降低或有障礙之高齡者正於增加中。對於此等 讀劑進行經口投^藥物時，產生服藥困難之問.題。另7 一 ί忙碌的現代社會裡，由無需選擇時間或場所即可 ^用之有利點而言，期待研究開發於服用時不需要水、+ 定且低容量而攜帶方便之經σ製劑。本發明研究者 : 。=獲:改善其服用性的氨氯地平之口腔内崩解性 @上述，表現口腔内崩解料之機能而不 布處理之製劑，並沒有可達成氨氯地平之光安定化之 2方法。所以，本發明研究者㈣為如果可提供不施以 對光安定之氨氯地平之鍵劑，即可應用於口腔内崩 产斤本I明研九者等經銳意探討，結果發現調配氧化鐵於 氨氯施平或其藥學上容許之鹽，就不需要用以光安定化之 =覆層，/ρ可非常簡便地獲得光安定化之含有氨氯地平之 經口固形組成物。又發現藉由應用該技術，調配氧化鐵於 氨^地平或其藥學上容許之鹽，即可非常簡便地使服用性 優異之π腔内崩解型製劑加以光安定化，而完成了本發明。 318705 9 200819144 亦即，本發明有關下列項目·· 乂 []種§有（a)氨氯地平（Amlodipine)或其藥學上容 許之I及（b)氧化鐵，且不具有被覆層之經口固形組成物。 [2]如上述[1]項所記载之經口固形組成物，其中， 質上不含氧化鈦。 、 、 [3 ]如上述[1 ]或[2 ]項所記载之經口固形組成物，苴 口腔内崩解型製劑。 /、/、 癱、[4]如上述丨1]至[3]項中任一項所記載之經口固形組 成物，其中，含有下列（3)至（(1)成分： (a) 氨氯地平或其藥學上容許之鹽， (b) 氧化鐵， (c )甘露糖醇， (d)玉米殿粉。 、[5]如上述[丨]至U]項中任一項所記載之經口固形組 成物，其中’更含有富馬酸硬脂酯鈉，且該經口固形組成 •物係口腔内崩解錠。 [6]如上述[5]項所記載之經口固形組成物，其中， 曰该（a)氨氯地平或其鹽在該經口固形組成物中之含 置’以氨氯地平計，為2至5重量％， 该（b)氧化鐵在該經口固形組成物中之含量為〇 2重量％， 量為70至 該（c)甘露糖醇在該經口固形組成物中之含 90重量％， 該（d)玉米澱粉在該經口固形組成物中之含量為5至 318705 10 200819144 1 5重量％，且 :(e)該富馬酸硬脂_在該經口固形組成物中之含量 ，為1至3重量％。 ⑴如上述[1]至[6]中任—項所記載之經口固形組成 物，其中，6亥氧化鐵係黃色三氧化二鐵。 [8]如上述[1]至[7]項中任一項所記載之經口固形組 成物，其中，含有（a)氨氯地平或其藥學上容許之鹽、及⑻ 氧化鐵之混合物。 、[9]如上述[丨]至[8]項中任一項所記載之經口固形組 成物其中，3有將（a)氨氯地平或其藥學上容許之鹽、及 (b)氧化鐵之混合物經造粒而得的組成物。 [發明之效果] 根據本發明可非常簡便地提供含有光安定性之氨氣地 平之經口固形組成物。又，因此可使無法施予塗布之氨氯 地平之口腔内崩解錠等易服用性製劑藉由光安定化所帶來 _之貝加以維持’提供使⑧齡者等吞儀困難之病患或忙綠 生活者在任何情形下皆可容易服用之光安定性之氨氯地平 之經口固形組成物。 【實施方式】 ， 由於氨氯地平，即[2-(2-胺基乙氧基甲基）_4_(2_氯苯 基^ 4 一氫-6-甲基吡啶-3, 5-二羧酸3-乙酯5-甲酯;|具 有光予活性中心，所以存在有（s)_(_)異構物及（E) —( + )異 構物，於本發明中可使用該等任一者或其混合物。其中以 使用（s)-(-)異構物及外消旋物為較佳。 318705 11 200819144 氨氯地平之藥學上容許之鹽，列舉例如與鹽酸、氯淺 •酸、硫酸、璘酸、乙酸、馬來酸、富馬酸、乳酸、酒石酸 ，捧檬酸、葡萄糖酸、琥轴酸、水揚酸、甲石黃酸、苯石盖酸、 甲苯磺酸等所構成之鹽。其中以與苯磺酸所成之鹽 磺酸氨氯地平（Amlodipine Besylate)為較佳。 产本發明中之氧化鐵，例如黃色三氧化二鐵、氧化鐵普、 二乳化-鐵、氧化鐵紅及氧化鐵黑，其中，以黃色 二鐵、氧化鐵黃、三氧化二鐵為較佳，以普 一 為更佳。 /、巴一虱化一 劑型之適切的調配量’隨著所調配之氧化鐵 如在含有黃色三氧化二鐵之旋劑時 過少則無法獲得充分之效果，所以 心:：配 至10咖圍内，更佳之添加量為 爭社少决上B 7里巧01至5重量％， f “’取佳之添加量為0.05至〇5重量％。 毛明中之氧化鐵之粒徑，就 只要是可均-分散、調配於經口固形 中，以0·01至、π f 〇.01至為佳q 本發明中之-二ίΠ，以〇.1至0· ^m為更佳 (_i)劑、乾二.Λ t例如谬康劑、軟糖 錠劑、可噪式制’政弹、細粒劑、顆粒劑等粒狀製劑 式製制、口腔内崩解型製劑等劑型之製劑。， 318705 12 200819144 :中就服用時不需用水，無需選擇時間所 點’以膠凍劑、軟糖劑、可 °服用之觀 ·.為較佳，更佳為口^ ^ "衣」、口腔内崩解型製劑 最佳。為腔内朋解型製劑’尤以口腔内崩解錠為 S月層係指覆蓋在直接經口投予單位之最 .),^^PTP(press thro-h 結合二 =1::1°列舉在將主藥物、賦形劑、崩解劑、 一 ：乾式4粒或濕式造粒等，必要時異、# 4 等成形而得之經口固带彡* L 、 仃打叙 溶液予以嘖霧C 將薄膜形成性之高分子 ,_ / 、、坐乾耜等於該經口固形組成物之外側，形 =於該經口固形組成物之組成的外層。上^ ^子溶液中，在不阻礙一般薄膜形成之範圍= :種添加劑。塗布係指形成此等被覆層。 其他之被覆層’例如列舉軟㈣或硬膠囊等膠囊。 本發明中，氨氯地平或其藥學上容許之鹽的含量雖無 厶=之:是由於一般一日投予量為2.5至㈣，所以 考衣劑之大小’以氨氯地平計，以含有氨氯地平或其藥 學上容許之鹽至1()重量“調配為佳。其中，以含有 氨f也平或其藥學上容許之鹽成為U5至6.25重量％而調 配’、、、4c仏，以含有1至6. 25重量％而調配為更佳，尤以含 有成為2至5重量％而調配為最佳。 本發明中之口腔内崩解型製劑係指不需要水即快速溶 解或崩解於口腔中而可服用，亦可與一般製劑同樣地和水 318705 13 200819144 .-起服用的製劑。其劑型列舉如散劑、細粒劑、顆 粒狀製劑及錠劑。 ' 本么月中之口腔内崩解型粒狀製劑、口腔内崩解鍵， 在口腔内之溶解或崩解所需時間通常為】分鐘内，其中， 較佳為45秒鐘内，更佳為3〇秒鐘内。 ▲本务明中之口腔内崩解型製劑中，由服用性之觀點而 言’賦形劑以添加水溶性賦形劑為佳。該水溶性賦形 例如服用時具有良好甜味之水溶性糖醇、糖類，具有甜 之胺基酸類及此等之混合物等，其中以水溶性糖醇、糖類、 甘胺酸及此等之混合物為較佳，尤以水溶性糖醇為最佳。 本發明中之水溶性糖醇係指例如水中加入lg之糖 醇每5分鐘強力混搖30秒鐘，約在30分鐘之内 使其洛解時’所必要之水量未滿3Gml的糖醇等。該水溶性 ::之：如山梨糖醇、甘露糖醇、麥芽糖醇、還原澱粉糖 物、木糖醉、異麥芽酮糖醇（騎〇geneted palatinose， ?/latinit)、赤藻糖醇等，或其2種以上以適切比率混 =用亦可。其中’較佳之水溶性糖醇之例如甘露糖醇、 木糖醇、赤藻糖醇，再以甘露糖醇、赤藻糖醇為更佳 以甘露糖醇為最佳'。本發明中，水溶性糖醇 士 例如在50至99.9重量圍内，其中以7。至1； 佳，以7〇至9〇重量%為更佳，尤以75至85重 $ %為最佳。 崩解梅中，特別以崩解性觀點而 3有朋解劑為佳。該崩解劑之例如澱粉、羧τ基纖 318705 14 200819144 •維素、魏曱基纖維素納、It甲基纖維素飼、低取代度經丙 -基纖維素、It甲基殿粉納、低取代錢ψ基殿粉納、交聯 ‘·竣甲基纖維素納（Cr〇Scarmellose s〇diun〇、交聯聚維酉同 (Cr〇SP〇Vid〇ne)等，此等可將2種以上以適切比率混合而 使用。其中，以殿粉、繞曱基纖維素約、低取代度經丙基 纖維素、羧甲基澱粉鈉、交聯羧甲基纖維素鈉、交聯聚維 酮為較佳。以澱粉、低取代度羥丙基纖維素、 澠於 鈉、交聯羧曱基纖維素鈉、交聯聚維嗣為更佳，更以^米分^ ’低取代度羥丙基纖維素為尤佳。最佳為澱粉。 本發明中之澱粉係指包含可使用於醫藥品之所有源自 於天然澱粉之澱粉。例如馬鈴薯澱粉、玉米澱粉、小麥澱 粉、稻米澱粉或可溶性澱粉、局部α化澱粉、α化澱粉= 經丙基化澱粉等，其中以玉米澱粉為較佳。該等殺粉含量 例如以1至50重量❹/〇為佳，其中以2至3〇重量％為較佳， 以3至20重量％為更佳，尤以調配5至15重量％為最佳。 本發明之口腔内崩解型製劑中，所使用結合劑並無特 別限制，例如殿粉（包括局部粉）、㈣基纖維素、 L丙基曱基纖維素、聚乙烯吼ρ各烷酮、明膠、甲基纖維、 ***膠粉末、聚乙烯醇、烧基與乙基纖維素等。就崩解 解觀1言’以實質上不使錢粉之外之物為理想。 所=貝質上係指只要是在不影響該口腔内崩解型製劑，护 別是在不影響口腔内之溶解或散解速度、及本發明之光: 定化效果的使用量範圍内，可容許其他結合劑之調配。文 本發明之經口固形組成物中，除上述成分之外，尚可 318705 15 200819144 :領域中一般使用之無毒性且惰性之添加劑。該等 口…丨貝貝上不衫響本發明之效果，-般作為醫筚 :力，丨而添加者。例如乳糖、玉米殿粉、甘露糖醇：木 山梨糖醇、赤藻糖醇、甘胺醇、滑石、高嶺 =Γ硫叫蝴、結晶纖物 纖二：：硬脂酸鈣：富馬酸硬脂酯鈉等潤滑劑；羧曱基 私田…巧低取代度㈣基纖維素、敌甲基殿粉鈉、交聯 =基纖維素鈉等崩解劑；經丙基纖維素、經丙基甲基纖 古’、、聚乙烯料烧酮、明膠、甲基纖維素、***膠粉 、聚乙稀醇、燒基經乙基纖維素等結合劑；其他之著色 :卜,味劑、香料、吸附劑、防腐劑、安定化劑、濕潤劑、 抗靜電劑、酸鹼值調整劑等。 〜製造本發明之錠劑時會使用潤滑劑，其中以硬脂酸鎂 及富馬酸硬脂酯鈉為適用。 另外’也可調配有阿斯巴甜 '醋磺内酯鉀（acesulfame K):糖精、糖精鈉、甜菊、蔗糖素（sucra 1 ose)等高甜味度 人造甜味料，或薄荷、綠薄荷、薄荷腦、檸檬、橙、葡萄 柚、鳳梨、水果、優格等賦香劑•香料等。特別是調配有 阿斯巴甜及薄荷系香料時，可得更佳之服用感覺。 本發明之經口固形組成物之製造方法，可採用周知方 例如造粒方法有擠壓造粒法、破碎造粒法、乾式壓密 粒法、流動層造粒法、轉動造粒法、轉動流動層造粒法、 巧逮授拌造粒法；製錠方法有例如濕式製錠法，直接製錠 法等。 16 318705 200819144 以下列舉實施例及比較例，更為具體說明，惟本發明 不侷限於其範圍。 實施例1 錠劑配方（mg) [表1 ]200819144 IX. INSTRUCTIONS: 广广 [Technical field to which the invention belongs] / The present invention relates to an oral solid composition and preparation containing amlodipine, which enhances photostability. [Prior Art] Amlodipine (Am 1 odi pi ne) which belongs to the dihydrogen 11-bite dance antagonist, has anti-hypertensive treatment due to its sufficient and constant vasodilating action and difficulty in causing tachycardia. The method plays an important role. However, amlodipine is a compound which is not easily photodecomposed in the dihydroabiidine compound, but decomposes when the amount of exposure is large to lower its function as an activating substance. Therefore, the oral solid composition containing amlodipine requires a technique for ensuring the stability of light. In the past, for the formulation of drugs which are unstable, there are known methods for the stabilization of various kinds of music. For example, in the patent document, a soft capsule in which a coloring agent is dispersed in a film is disclosed, and nifedipine which is a drug which is unstable to light is enclosed, and the softness of nifedipine which is decomposed or deteriorated by light is prevented. capsule. Further, the patent document discloses a capsule preparation in which an activated vitamin (10) is formulated by a hard capsule containing: a dye or a red iron oxide. These techniques all contain a coloring agent in a capsule film which is coated with light and is unstable, and is difficult to apply to tablets, granules, fine granules, powders and the like. On the other hand, Patent Document 3 discloses that a tablet of a dihydropyridine derivative is coated with a film in which iron oxide is formulated to form a tablet which is stable to light. However, this technology increases the coating step, the time and labor required 318705 5 200819144 : Increases and increases production costs. In addition, it is necessary to divide and use (4), and it is easy to cause trouble because the coating line is masked, and the blade surface is exposed after the division, and the light stabilization effect cannot be expected. Furthermore, the above technique cannot be applied to a formulation which cannot be subjected to coating engineering for some reason. For example, an orally disintegrating preparation may damage its rapid disintegration and rapid solubility in the oral cavity when it is applied as a whole, and its function cannot be exhibited. In addition, although the rapid disintegration of the preparation can be maintained by coating only the raw material medicine in the preparation or the particles containing the raw material medicine, at this time, part of the coated preparation in the oral cavity does not disintegrate and dissolve, This point predicts that it is very difficult to take e-learning agents. X, Patent Document 4 discloses a light-stabilizing pyridine-based compound containing oxidized oxime as a light-shielding agent and containing edible yellow No. 5, ferric oxide, and yellow ferric oxide as colorants. However, the features disclosed in the literature are based on the solid dispersion of arididipine by a suitable excipient, and the coating liquid containing the coloring agent and the sunscreen is sprayed. The preparation of the covered product is disclosed (the second page of the patent document 4, the first block, the first row, the fifth row, the second row, the fourth row, the second page, the second, the third row, the third row, the third page, the fourth block, the fifth The example of the line). In the light stabilization method in which a coated tablet, granule, fine granule, or powder is not applied, Patent Document 5 discloses that one or more substances selected from the yellow and red coloring agents are formulated in a light-labile fat. A composition that enhances light stability by a soluble drug. Further, Patent Document 6 discloses an oral solid composition obtained by wet granulation in which a coloring agent is added to a powder containing a photolabile drug. Further, Non-Patent Document i discloses the addition of yellow 318705 6 200819144 two-color two, and in the case of nifedipine, it is possible to suppress the generation of oxides due to light and to suppress the decrease in the content of the main music. However, this document is related to the description of helmets and amlodipine. ..., Patent Document 1: Japanese Laid-Open Patent Publication No. 55-22645. Patent Document 2: Japanese Laid-Open Patent Publication No. Hei-4-46122. Patent Document 3: Japanese Laid-Open Patent Publication No. 2003-104888. Patent Document 4: Japanese Laid-Open Patent Publication No. 2003-104887. _ Patent Document 5: Japanese Laid-Open Patent Publication No. Hei 2-7-583. Patent Document 6: Japanese Laid-Open Patent Publication No. 2000-191516. Non-Patent Document 1: International Pharmaceutical Journal (Internati〇nal J〇urnai f Pharmaceutics), Issue 1, 3, 1994, pp. 69-76. SUMMARY OF THE INVENTION [Problems to be solved by the invention] The problem to be solved by the present invention is to provide a light stability which can be easily prevented from discoloration and decomposition by amlodipine or a pharmaceutically acceptable salt thereof due to light. • A modified oral solid composition. [Means for Solving the Problem] The hydrazine-based compound and t, due to the light stability of amlodipine, are not a problem in the range of use as a general pharmaceutical product. The inventors of the present invention found that amlodipine differs from the fact that it has a discoloration in the range where the content of light is not detected. 2 Prevention of such coloration is a research subject. In the above Non-Patent Document 1, the f color is completely undescribed. Naturally, there is no description or darkness about this subject. The subject of the 5 Hai literature is to improve the nifedipine lozenge in the light of 400 singer light 318705 7 200819144 (w-Candle) for 14 days, there will be 45% decomposition, on the other hand, as shown in the following test example, The amount of money produced by the agent is about 1%, and the degree of decomposition is completely different. = The main problem of amlodipine is to prevent coloration. It is known that it is completely different from the content reduction of the main subject of Shi Xiao. It has also been found by the inventors and the like that the coloring behavior itself is completely different from that of the sulfonate, that is, the actual silking agent is confirmed, and the nifedipine is prepared in the same manner. The tablets in the Ding and Ding Ding are placed in the tile first. The color is not changed. In the nifedipine opening, the color is in the color of the stone, and the original color is yellow. It fades in a few hours, and the color is slightly yellowish in the case of amlodipine in the case of amlodipine. It can be seen that the color reaction of the clamped color reaction and the color reaction of amlodipine are completely different. The method of whether the air quality of the first method can be applied to the 6th Λ Λ is obviously impossible. Ingredients, the raw materials of the literature 5 and a, the tolerant effective is tetramethine (menate calorie (6) and Sodecone (Sofalcone), not only does not check the heat of the '', the second hydrogen. :::Up=The effect of the same structure leveling. It is more difficult to predict the ammonia chloride_f progress from the above literature. The inventors of the present invention also found that the test example is as follows: the titanium oxide is formulated into t-amyldipine. Conversely, it will promote the use of stabilizers for the decomposition of light;;! Also, as an anti-oxidant, such as butylhydroxytoluene, butylhydroxy alum, 318705 8 200819144 ether, as an antioxidant, these antioxidants are It can suppress the production of decomposition products caused by ammonia chloride, but it is also found that at least on the ammonia level, the light caused by the light means the same behavior. Therefore, the iron oxide is mixed with ammonia to suppress the color change effect. The system is completely unpredictable. With the evolution of the aging society, due to various physiological functions, such as low cattle or dementia, the function of ingesting food (eg, (4) the age of the temple is reduced or the number of elderly people with disabilities is increasing. Such reading agents In the case of oral administration of drugs, it is difficult to take medication. In another busy modern society, it is not necessary to choose the time or place to use it. Water, + and low capacity and convenient to carry sigma preparation. The present inventors: 1. = obtained: the oral disintegration of amlodipine which improves the administration of the above @, which shows the function of the disintegration in the oral cavity There is no method for achieving the light stabilization of amlodipine in the preparation without treatment. Therefore, the inventors of the present invention (4) can be applied if a key agent for amlodipine which is not stable to light can be provided. Oral collapse in the mouth of the mouth, I Mingyan nine and so on, after careful investigation, found that the distribution of iron oxide in ammonia chloride or its pharmaceutically acceptable salt, you do not need to use light stabilization = coating, / ρ It is very easy to obtain a light-stabilized oral solid composition containing amlodipine. It has also been found that by applying this technique, iron oxide can be easily administered to amlodipine or a pharmaceutically acceptable salt thereof. Excellent π-cavity disintegration preparation The present invention has been completed by light stabilization. 318705 9 200819144 That is, the present invention relates to the following items: 乂[] § has (a) amlodipine or its pharmaceutically acceptable I and (b) The oral solid composition according to the above-mentioned item [1], wherein the titanium-containing composition is not contained in the above-mentioned item [1], and [3] is as described above. Oral solid composition as described in [1] or [2], orally disintegrating preparation. /, /, 瘫, [4] as described in any of the above items ]1] to [3] The oral solid composition comprising the following (3) to ((1) component: (a) amlodipine or a pharmaceutically acceptable salt thereof, (b) iron oxide, (c) mannitol, d) Corn house powder. [5] The oral solid composition according to any one of the above-mentioned items, wherein the composition further comprises sodium stearyl fumarate, and the oral solid composition comprises an oral cavity collapse. Unsinking. [6] The oral solid composition according to the above [5], wherein the (a) amlodipine or a salt thereof is contained in the oral solid composition, and is determined by amlodipine. 2 to 5% by weight, the content of the (b) iron oxide in the oral solid composition is 〇2% by weight, and the amount is 70 to 90% of the (c) mannitol in the oral solid composition % by weight, the content of the (d) corn starch in the oral solid composition is 5 to 318705 10 200819144 15 5 % by weight, and: (e) the fumaric acid stearin - in the oral solid composition The content is from 1 to 3% by weight. (1) The oral solid composition according to any one of the above [1] to [6] wherein the iron oxide is yellow iron oxide. [8] The oral solid composition according to any one of the above [1] to [7], which comprises (a) amlodipine or a pharmaceutically acceptable salt thereof, and (8) a mixture of iron oxide. [9] The oral solid composition according to any one of the above-mentioned items, wherein (a) amlodipine or a pharmaceutically acceptable salt thereof, and (b) oxidation A composition obtained by granulating a mixture of iron. [Effects of the Invention] According to the present invention, it is possible to provide a mouth-solid composition containing a light-stabilizing ammonia gas level very easily. In addition, it is possible to maintain the easy-to-use preparation such as the orally disintegrating tablet of amlodipine which cannot be applied, by the light stabilization, and to provide a patient who is difficult to swallow the body such as an 8-year-old person. Or a solid solid composition of amlodipine which is easy to take under any circumstances. [Embodiment], due to amlodipine, ie [2-(2-aminoethoxymethyl)_4_(2_chlorophenyl^4-hydro-6-methylpyridine-3, 5-dicarboxylic acid 3-ethyl 5-methyl ester; | has a photoactive center, so there are (s) _ (-) isomers and (E) - ( + ) isomers, which can be used in the present invention One or a mixture thereof, wherein the (s)-(-) isomer and the racemate are preferably used. 318705 11 200819144 A pharmaceutically acceptable salt of amlodipine, for example, with hydrochloric acid, chlorine, and acid , sulfuric acid, citric acid, acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, gluconic acid, succinic acid, salicylic acid, tartaric acid, benzoic acid, toluene sulfonic acid, etc. The salt is composed of amlodipine Besylate which is formed with benzenesulfonic acid. The iron oxide of the present invention is produced, for example, yellow ferric oxide, iron oxide, and double emulsion-iron. , iron oxide red and iron oxide black, of which yellow diiron, iron oxide yellow, ferric oxide are preferred, and Puyi is better. /, Ba Yihuan one dosage form of the appropriate amount As the prepared iron oxide is too small in the case of a yellow iron oxide-containing spinner, sufficient effect cannot be obtained, so the heart:: is allocated to 10 coffee, and the better addition amount is for the competition. Li Qiao 01 to 5 wt%, f "' is preferably added in an amount of 0.05 to 5% by weight. The particle size of the iron oxide in the hair, as long as it can be uniformly dispersed, blended in the oral solid, to 0. 01 To, π f 〇.01 to be a good q in the present invention - Π Π, with 〇.1 to 0 · ^ m is better (_i) agent, dry two. Λ t such as 谬 Kang agent, gummy lozenge Formulations of granule preparations such as granules, fine granules, granules, etc., orally disintegrating preparations, etc., 318705 12 200819144: No need to use water when taking, no need to choose time The point of 'quick, soft candy, can be taken ° °.. is better, better for the mouth ^ ^ " clothing, oral disintegration preparation is the best. 'In particular, the intraoral disintegrating ingot is the S month layer refers to the most direct oral administration unit.) ^^PTP (press thro-h combined with two = 1::1° listed in the main drug, Excipients, disintegrating agents, one: dry type 4 or wet granulation, etc., if necessary, the resulting solid tape 彡* L, 仃 叙 溶液 啧 啧 啧 啧 啧The polymer, _ / , , sitting dry is equal to the outer side of the oral solid composition, the shape = the outer layer of the composition of the oral solid composition. In the upper ^ ^ solution, does not hinder the formation of general film Range =: Kind of additive. Coating refers to the formation of such coating layers. Other coating layers 'for example, capsules such as soft (four) or hard capsules. In the present invention, the content of amlodipine or a pharmaceutically acceptable salt thereof is not determined as follows: since the usual daily dosage is 2.5 to (4), the size of the coating agent is determined by amlodipine. It is preferred that amlodipine or a pharmaceutically acceptable salt thereof is added to the weight of 1 (). Among them, ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, It is preferably formulated to contain 1 to 6.2 wt%, more preferably 2 to 5 wt%. The orally disintegrating preparation in the present invention means rapid dissolution or disintegration without the need of water. It can be taken in the oral cavity, and it can also be taken in the same manner as the general preparation and water 318705 13 200819144. The dosage form is exemplified by powders, fine granules, granule preparations and lozenges. The time required for dissolution or disintegration in the oral cavity in the orally disintegrating granular preparation or the intraoral disintegration bond is usually within a minute, preferably within 45 seconds, more preferably within 3 seconds. ▲In the oral cavity disintegration preparation of the present affairs, from the point of view of taking Preferably, the water-soluble excipient is added by adding a water-soluble excipient, for example, a water-soluble sugar alcohol having a good sweet taste when taken, a saccharide, a sweet amino acid, and the like, wherein the water-soluble sugar Alcohol, saccharide, glycine and mixtures thereof are preferred, especially water-soluble sugar alcohols. The water-soluble sugar alcohol in the present invention means, for example, the addition of lg of sugar alcohol in water every 5 minutes. In seconds, when it is released within about 30 minutes, the amount of water required is less than 3Gml of sugar alcohol, etc. The water solubility:: such as: sorbitol, mannitol, maltitol, reduced starch sugar , xylose, isomalt (gianted palatinose, ?/latinit), erythritol, etc., or two or more thereof may be mixed at appropriate ratios. Among them, the preferred water-soluble sugar alcohol For example, mannitol, xylitol, erythritol, and mannitol, erythritol are more preferably mannitol. In the present invention, the water-soluble sugar alcohol is, for example, at 50 to 99.9 weights, of which 7 to 1; good, 7 to 9 weight% is better, especially 75 to 85 $ % is the best. Disintegration of plum, especially in terms of disintegration, 3 is better. The disintegrating agent is, for example, starch, carboxy τ-based fiber 318705 14 200819144 • Vitamin, Wei-based cellulose, It Methyl cellulose feeding, low substitution degree of propylene-based cellulose, It's methyl methacrylate powder, low substitution of ψ ψ 殿 殿 、, cross-linking '·竣 methyl cellulose nano (Cr〇Scarmellose s〇diun〇 , cross-linked poly-dimensional (Cr〇SP〇Vid〇ne), etc., these two or more can be mixed at a suitable ratio. Among them, the powder, the ruthenium-based cellulose, low substitution C Cellulose, sodium carboxymethyl starch, croscarmellose sodium, and crospovidone are preferred. It is more preferable to use starch, low-substituted hydroxypropylcellulose, sodium strontium, croscarmellose sodium, crosinized quinone, and hydroxypropylcellulose with low substitution degree. Especially good. The best is starch. The starch in the present invention means a starch which is derived from all natural starches which can be used for pharmaceuticals. For example, potato starch, corn starch, wheat starch, rice starch or soluble starch, partially gelatinized starch, gelatinized starch = propylated starch, etc., among which corn starch is preferred. The powdericidal content is, for example, preferably from 1 to 50% by weight, more preferably from 2 to 3% by weight, more preferably from 3 to 20% by weight, most preferably from 5 to 15% by weight. . In the orally disintegrating preparation of the present invention, the binding agent to be used is not particularly limited, and examples thereof include, for example, a topical powder (including a topical powder), a (tetra)-based cellulose, a L-propyl mercapto cellulose, a polyvinyl anthracene ketone, Gelatin, methyl fiber, gum arabic powder, polyvinyl alcohol, alkyl and ethyl cellulose. In the case of disintegration, it is said that it is not ideal for things other than money powder. The term "beauty" means that as long as it does not affect the orally disintegrating preparation, the protection is in a range that does not affect the dissolution or disintegration rate in the oral cavity, and the use amount of the light of the present invention: Other binders can be tolerated. In the oral solid composition of the present invention, in addition to the above ingredients, it is possible to use 318705 15 200819144: a non-toxic and inert additive generally used in the field. These mouths... 丨 丨 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝 贝For example, lactose, corn house powder, mannitol: sorbitol, erythritol, glycine, talc, kaolin = sulphur called butterfly, crystal fiber fiber II: calcium stearate: fumarate Lubricating agent such as sodium ester; carboxy thiol-based private field... skillful low degree of substitution (tetra)-based cellulose, dimethoprim sodium, cross-linking = sodium cellulose and other disintegrants; propyl cellulose, propyl Methyl cellulose, polyethylene ketone, gelatin, methyl cellulose, gum arabic powder, polyethylene glycol, alkyl acetate and other bonding agents; other colors: Bu, flavor, spices , adsorbents, preservatives, stabilizers, wetting agents, antistatic agents, pH adjusters, etc. ~ A lubricant is used in the manufacture of the tablet of the present invention, wherein magnesium stearate and sodium stearyl fumarate are suitable. In addition, 'acesulfame K can be added with acesulfame K: high-sweet artificial sweeteners such as saccharin, sodium saccharin, stevia, and sucra ose, or mint and spearmint , menthol, lemon, orange, grapefruit, pineapple, fruit, yoghurt and other scenting agents and spices. Especially when blended with aspartame and mint flavors, you can get a better feeling. The method for producing the oral solid composition of the present invention can be carried out by a known method such as granulation method, extrusion granulation method, crush granulation method, dry compact granulation method, fluidized bed granulation method, rotary granulation method, rotation The flow layer granulation method and the granulation method are used for the granulation method; for example, the wet tableting method, the direct tableting method, and the like. 16 318705 200819144 The following examples and comparative examples are described in more detail, but the invention is not limited thereto. Example 1 Lozenge Formulation (mg) [Table 1]
※1商品名：D-甘露糖醇（協和發酵工業公司製品） ※2商品名：玉米澱粉（XX16)W(日本食品化工公司製品） ^ 商品 * : PRUV(Pe聰st Pharmaceuticals 公司（美國） 製品） 則商品名··黃色三氧化二鐵（癸已化成公司製品 318705 200819144 ※5商品名·二氧化二鐵（癸已化成公司製品） 6商品名：精製去砷氧化鈦（薩克多累勉化學公司（德 國）) ※了商品名：3-第三丁基-4-羥基苯甲醚（Nacalai tesque 公司製品） ※8商品名：2,6-二第三丁基-對曱齡（Nacalai tesque公 司製品） ※9商品名：食民黃色5號（三榮源F· F· I·公司製品） 鲁※10商品名·食用黃色5號|呂色殿（三榮源F.F.I公司製 品） 商品名：食用紅色5號（三榮源F.F· I·公司製品） ※12商品名·食用紅色1〇2號（三榮源F.F.I·公司製品） 實施例1至3及比較例1至8係按照表1中所示配方， 將該配方之12倍量之各組成分以乳鉢充分混合後，秤取一 錠配方量使用油壓式壓製機（理研公司製品）以50kgf之壓 鲁力屋备§ ’獲得直控為7mm之鍵;劑。 試驗例 就實施例1至3及比較例1至8之製劑，實施光安定 性試驗。將在螢光燈4〇〇〇勒克司（iux)歷經2星期之外觀 及氧化物之產量之結果示於表2。又，氧化物（2-[(2-胺基 乙氧基）甲基]-4-（鄰氯笨基）一6-曱基-3, 5-吨啶二羧酸3- 乙醋5-曱酯）之定量係藉由液體層析法而分析。 H_PLC分析竺^ 管柱··十八烷基結合型矽膠（平均粒徑為5 // m，内徑 18 318705 200819144 為4. 6mm，長度為15〇mm)(商品名為⑶*1 Product name: D-mannitol (product of Kyowa Fermentation Co., Ltd.) *2 Product name: Corn Starch (XX16) W (product of Japan Food Chemical Co., Ltd.) ^ Commodity* : PRUV (Pe Sung St Pharmaceuticals Co., Ltd. (USA) Products ) Product Name··Yellow Ferric Oxide (Products of 癸 化 成 成 成 成 318705 200819144 ※5 Product Name·Ethylene Oxide (Products of 癸化化成公司) 6 Product Name: Refined arsenic oxide (Sakdo 勉Chemical company (Germany) ※ Product name: 3-tert-butyl-4-hydroxyanisole (product of Nacalai tesque company) *8 Trade name: 2,6-di-tert-butyl-pair age (Nacalai Tesque company product) ※9 product name: food person yellow No. 5 (sanrong source F· F· I· company product) Lu ※10 product name · edible yellow No. 5 | Lu Seiya (San Fung Yuen FFI company products) Name: Edible Red No. 5 (Sanyungwon FF·I·Company Products) ※12 Product Name·Edible Red No.1 (Sanyeon FFI·Company Products) Examples 1 to 3 and Comparative Examples 1 to 8 are in accordance with The formula shown in Table 1 is divided into 12 parts of the composition and mixed with chyle. After the combination, the amount of the formula is taken using a hydraulic press (manufactured by Riken Co., Ltd.) to obtain a key of 7 mm directly controlled by a pressure of 50 kgf. The test examples are as shown in Examples 1 to 3 and compared. The photosensitivity test was carried out for the preparations of Examples 1 to 8. The results of the appearance and oxide yield of the fluorescent lamp 4 iux (iux) for 2 weeks are shown in Table 2. Further, the oxide (2) -[(2-Aminoethoxy)methyl]-4-(o-chlorophenyl)- 6-mercapto-3, 5-tonidinedicarboxylic acid 3-ethylacetate 5-decyl ester) Analysis by liquid chromatography. H_PLC analysis 竺^ tube column · octadecyl-bonded tannin (average particle size is 5 // m, inner diameter 18 318705 200819144 is 4. 6mm, length is 15〇mm) (trade name is (3)
Nacalai tesque 公司製品） A液：3〇mm〇i/L填酸鹽緩衝谈（邱6 〇)/曱醇混合液 (1:1) β液：甲醇/30mmol B液· 80%—〇%之梯 檢測器：紫外光。 檢測波長：237nm。 [表2 ]Nacalai tesque company) A liquid: 3〇mm〇i/L acid salt buffer (Qiu 6 〇) / sterol mixture (1:1) β solution: methanol / 30mmol B solution · 80% - 〇% Ladder detector: UV light. Detection wavelength: 237 nm. [Table 2 ]
磷酸緩衝液（ρΗ6· 〇)混合液（19 : 1) 度。 平之1/2 (氧化物量係HPLC之面積百分率值乘以校正係數之2 的數值（由於氧化物之紫外光吸收強度為氨氯地 得 所致））。 318705 19 200819144 •由表2可知，比較例1之完全未進行光安定化之製劑， '其外㈣化大’氧化物之產量亦超過1%。相對於此，比較 ‘例.2之含有氧化鈦之製劑，不僅未抑制變色，氧化物產生 量亦反而增加。施予被覆層而達成光安定化之方法，一般 以使用遮光效果強大之氧化鈦而進行塗布，卻發現替代塗 布而直接混合氧化鈦於主藥物及賦形劑等所製造之彭十 反而氨氯地平之光安定性會劣變。因此，讀知一般所^以 將被覆力強大之物質與主藥物或賦形劑等混合之方法而可 獲得光安定化的想法，不能適用於氨氣地平。 又，比較例3及4係添加作為抗氧化劑之丁基声 及，丁基經基甲苯而成之製劑，比較例6係添二用 5色5號鋁色澱之製劑’雖然皆能抑制氧化物之產量 ί無法抑制外觀變化。因此，可知添加抗氧化劑或色素：： 然效。 ’、白 分別添加食用黃色5號、食用黃色3號及食用紅色⑽ 唬寺其他黃色、紅色系色素之製劑的比較例5、7及8盆 外觀變化及氧化物產量皆無法抑制。因此，可知去、 一般皆無光安定化效果。 I， 由上述可知發現遮光劑、抗氧化劑、色素 抑制氧化物之產生及/或外觀變化，相對而言，實|,、、法 至3之含有黃色三氧化二鐵或三氧化二鐵之製劑1 抑制其外觀變化、氧化物產量。因此，使用一般方：， 二抑制外觀變化及氧化物產量，以氨氯地平及氧化施 4寸疋組合始能抑制外觀變化以及氧化物產量。 、’。之 318705 20 200819144 [產業上之利用可行性] : 依據本發明可簡便地防止氨氯地平（Amlodipine)或其 :藥學上容許之鹽由於光線所造成之變色及分解，而能提供 經光安定化之經口固形組成物。藉此，可提升氨氯地平或 其藥學上容許之鹽之口腔内崩解型製劑之品質，同時使簡 易而攜帶性優異之包裝形態成為可行，讓高齡者或忙碌之 現代社會人可方便地攜帶，不需攝取水在任何場地皆能容 易地服用氨氯地平或其藥學上容許之鹽類。 21 318705Phosphate buffer (ρΗ6· 〇) mixture (19: 1) degrees. 1/2 (the amount of oxide is the area percentage value of HPLC multiplied by the value of the correction factor of 2 (due to the ultraviolet absorption of the oxide is due to the ammonia chloride)). 318705 19 200819144 • It can be seen from Table 2 that the preparation of Comparative Example 1 which was not completely photo-stabilized, the yield of the 'outer (four) large' oxide was also more than 1%. On the other hand, in comparison with the preparation containing titanium oxide of Example 2, not only the discoloration was not suppressed, but the amount of oxide generation was also increased. The method of applying the coating layer to achieve light stabilization is generally applied by using titanium oxide having a strong light-shielding effect, and it is found that the titanium oxide is directly mixed with the main drug and the excipient, and the ammonia is produced instead of the coating. The stability of the light of the ground will deteriorate. Therefore, it is generally understood that the idea of light stabilization can be obtained by mixing a substance having a strong coating power with a main drug or an excipient, and the like cannot be applied to an ammonia gas level. Further, Comparative Examples 3 and 4 were prepared by adding a butyl group as an antioxidant and a preparation of butyl group-based toluene, and a comparative example 6 was added to a preparation of a 5-color No. 5 aluminum lake. The yield of the object ί cannot suppress the appearance change. Therefore, it can be seen that the addition of an antioxidant or a pigment:: is effective. </ br> White, respectively, Comparative Examples 5, 7 and 8 of the preparations of the edible yellow No. 5, the edible yellow No. 3 and the edible red (10) other yellow and red pigments of the 唬 Temple were not able to suppress the appearance change and the oxide yield. Therefore, it can be seen that there is generally no light stabilization effect. I, from the above, it is known that the generation of the sunscreen, the antioxidant, the dye inhibiting oxide, and/or the appearance change, and the preparation of the yellow iron oxide or the ferric oxide are relatively high. 1 Inhibit its appearance change and oxide production. Therefore, the use of the general side:, two inhibition of appearance changes and oxide yield, with amlodipine and oxidized 4 inch 疋 combination can inhibit the appearance of changes and oxide production. , '. 318705 20 200819144 [Industrial Feasibility]: According to the present invention, it is possible to easily prevent amlodipine or its pharmaceutically acceptable salt from providing light stability by discoloration and decomposition caused by light. The oral solid composition. Thereby, the quality of the orally disintegrating preparation of amlodipine or a pharmaceutically acceptable salt thereof can be improved, and at the same time, a simple and portable packaging form can be made feasible, so that an elderly person or a busy modern society can conveniently Carrying, without taking in water, can easily take amlodipine or its pharmaceutically acceptable salts at any site. 21 318705