200835526 九、發明說明： 【發明所屬之技術領域】 本發明係關於含有奧美沙坦酯 （olmesartan medoxomil)及阿折地平（azelnidipine)之安定的固形製 劑。 【先前技術】 現今，廣泛使用血管收縮素II受體拮抗劑及鈣離子通 道拮抗劑作爲高血壓症或心臟病等治療或預防用之醫藥。爲 腎素-血管收縮素系之抑制藥的血管收縮素II受體拮抗劑對 腎素依賴性之高血壓症特別有效，顯示出對於心血管或腎臓 障礙之保護作用。又，由於鈣離子通道拮抗劑除了具有血管 擴張作用外又具有鈉利尿作用，對於體液儲存性（腎素非依 賴性）之高血壓症亦有效。因此，若倂用血管收縮素Π受體 拮抗劑與鈣離子通道拮抗劑，由於除了有來自血管收縮素II 受體拮抗劑之腎素-血管收縮素系之抑制效果外，加上來自 鈣離子通道拮抗劑之血管平滑肌的鈣離子通道拮抗作用及 二次性鈉排泄作用，同時抑制複數種高血壓成因成爲可能， 而期待顯示不管病因爲何之安定且充分的高血壓症之治療 或預防效果。 (5-甲基-2-酮基-1，3-二氧戊環-4-基）甲基4-(1-羥基-1-甲基乙基）-2-丙基- l-[2’-( 1H-四唑-5-基）聯苯基-4-基甲基] 咪唑-5-羧酸酯（以下，稱爲奧美沙坦酯）爲優異的血管收縮素 II受體拮抗劑，已知作爲高血壓症及心臟病等治療或預防用 之醫藥爲有用的（日本專利第20825 1 9號公報、美國專利第200835526 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a solid formulation containing olmesartan medoxomil and azelnidipine. [Prior Art] Nowadays, angiotensin II receptor antagonists and calcium ion channel antagonists are widely used as medicines for treating or preventing hypertension or heart disease. Angiotensin II receptor antagonists, which are inhibitors of the renin-angiotensin system, are particularly effective against renin-dependent hypertension and exhibit protective effects against cardiovascular or renal pelvic disorders. Further, since the calcium channel antagonist has a sodium diuretic action in addition to the vasodilating action, it is also effective for humoral storage (renin non-dependent) hypertension. Therefore, if an angiotensin receptor antagonist and a calcium channel antagonist are used, in addition to the inhibitory effect of the renin-angiotensin system derived from an angiotensin II receptor antagonist, plus calcium ion The calcium channel antagonism and secondary sodium excretion of the vascular smooth muscle of the channel antagonist are possible, and it is possible to suppress the causes of a plurality of hypertension, and it is expected to show the therapeutic or preventive effect of hypertension regardless of the cause and stability of the disease. (5-Methyl-2-keto-1,3-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl- l-[2 '-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate (hereinafter referred to as olmesartan medoxomil) is an excellent angiotensin II receptor antagonist It is known to be useful as a medicine for the treatment or prevention of hypertension and heart disease (Japanese Patent No. 20825 1 9 and US Patent No.
200835526 5,6 1 6,5 99 號公報）。200835526 5,6 1 6,5 99 bulletin).
含有有效成分奧美沙坦酯5mg、10mg、2〇mg S 有作爲添加物之低取代度羥丙基纖維素、羥丙 晶纖維素、乳糖、硬脂酸鎂。 奧美沙坦酯由於咪唑環上有酯基而容易受 酸性或鹼性條件下經水解而變換爲活性代謝物 -1·甲基乙基）-2-丙基- l-[2’- ( 1H-四唑-5-基） 甲基]咪唑-5-羧酸（以下，稱爲RNH-6270 )。 錠被販售， ξ 40mg，及含 基纖維素、結 到水解等，於 之4 - ( 1 _經基 聯苯基-4-基The active ingredient olmesartan medoxomil 5 mg, 10 mg, and 2 mg of S have low-substituted hydroxypropylcellulose, hydroxypropylcellulose, lactose, and magnesium stearate as additives. Olmesartan medoxomil is easily converted to the active metabolite-1·methylethyl)-2-propyl-l-[2'- ( 1H) due to the ester group on the imidazole ring. - Tetrazolium-5-yl)methyl]imidazole-5-carboxylic acid (hereinafter referred to as RNH-6270). The ingot is sold, ξ 40 mg, and the cellulose-containing cellulose, and the hydrolysis to the like, in the 4 - (1 _-based phenyl-4-yl group)
又，（士）-2 -胺基-1,4 -二氫-6-甲基- 4- ( 3 -硝 吡啶二羧酸3-( 1-二苯基甲基吖丁啶基）酯5 基苯基）-3, 5- -異丙基酯（以 200835526 下稱爲阿折地平），爲優異的鈣離子通道拮抗劑，已知作爲 高血壓症及心臟病等治療或預防用之醫藥爲有用的（日本專 利第1 6 6 6 7 5 5號公報、美國專利第4，7 7 2，5 9 6號公報）。Further, (士)-2-amino-1,4-dihydro-6-methyl-4-(3-diphenylmethylazetidinyl) 3-ylbenzene Base,-3,5-isopropyl ester (hereinafter referred to as adipine in 200835526) is an excellent calcium channel antagonist and is known to be useful as a medicine for the treatment or prevention of hypertension and heart disease. (Japanese Patent No. 1 6 6 6 7 5 5, U.S. Patent No. 4,7 2 2, 5, 9 6).
阿折地平已有以Cal block® (註冊商標）錠被販售，含 有有效成分阿折地平8mg或16mg，及含有作爲添加物之D-甘 露糖醇、羧甲基纖維素鈣、低取代度羥丙基纖維素、碳酸氫 鈉、聚山梨酸酯8 0、偏矽酸鋁酸鎂、輕質矽酸酐、羥丙基纖 維素、滑石、硬脂酸鎂。 於先前技術中，組合奧美沙坦酯及阿折地平之醫藥爲已 知（國際公開第2004/067003號小冊），但並未知悉本發明 之含有奧美沙坦酯及阿折地平之安定的固形製劑。 專利文獻1 :日本專利第20 825 1 9號公報（美國專利第 5,6 1 6,5 99 號公報） 專利文獻2 :日本專利第1 6 6 6 7 5 5號公報（美國專利第 4,772,5 96 號公報） 專利文獻3 :國際公開第2004/067003號小冊。 【發明内容】 發明欲解決之問題 200835526 本發明之課題係提供含有奧美沙坦酯及阿折地平之安 定的固形製劑、及含有奧美沙坦酯及阿折地平之固形製劑 之安定化方法等。 近年來，高血壓患者有倂用含合倂症治療之藥劑的複 數種藥劑的傾向，此被指摘爲成爲血壓控制不良之一個原 因的可能性。 由於一旦服用的藥劑數多，服藥順從性會降低，爲了 實現確實的血壓控制，認爲企求患者服藥順從性之提升爲 重要的。血管收縮素II受體拮抗劑之奧美沙坦酯與鈣離子 通道拮抗劑之阿折地平，由於可期待有更確實的高血壓治 療效果之組合而於醫療場所中被廣泛倂用，爲使患者之服 藥順從性提升，強烈地冀望兩藥劑之調配劑之開.發。 一般而言開發含有2種類藥劑之固形製劑（調配劑） 時，經常於任一方單劑之處方上，再追加另一方有效成分 的處方。然而，含有奧美沙坦酯及阿折地平的固形製劑中， Olmetec⑧（註冊商標）錠、Calblock® (註冊商標）錠任一 者之處方作爲基礎的場合，亦知奧美沙坦及/或阿折地平之 物理或化學調配安定性會變差。此認爲係，因奧美沙坦酯 於驗性下具不安定的性質，但阿折地平於驗性具安定的性 質，於任一處方中添加另一方有效成分時，此添加的有效 成分會變得不安定。即認爲，因Calb lock (註冊商標）錠 之製劑處方爲鹼性，一旦於此加入奧美沙坦酯則奧美沙坦 酯會變得不安定，相反地，因Ο 1 m e t e c (註冊商標）錠之製 劑處方不爲鹼性，於此加入阿折地平時阿折地平會變得不 200835526 安定。 解決課題之手段 本發明者們爲解決上述課題致力硏究的結果，發現經 由將各別有效成分以彼此不接觸的方式分離調配，發現可 安定化含有奧美沙坦酯及阿折地平之固形製劑，遂而完成 本發明。 本發明爲提供含有奧美沙坦酯及阿折地平之安定的固 形製劑（特別是高血壓症之預防或治療用製劑）、製造前述 固形製劑（特別是高血壓症之預防或治療用製劑）用之奧 美沙坦酯及阿折地平之使用、將含有奧美沙坦酯及阿折地 平之藥理學上有效量之前述固形製劑投與溫血動物（特別 是人類）之預防或治療疾病（特別是高血壓症）的方法、 含有奧美沙坦酯及阿折地平之固形製劑（特別是高血壓症 之預防或治療用製劑）之安定化方法等。 亦即，本發明提供： (1 ) 一種固形製劑，其含有奧美沙坦酯及阿折地 平，其特徵在於該有效成分以互相不接觸的方式分離調配； (2 ) ( 1 )中記載之固形製劑，其中固形製劑爲錠 劑之形態； (3 ) ( 2 )中記載之固形製劑，其中錠劑爲多層錠， 奧美沙坦酯與阿折地平被調配於各別層中； (4) (3)中記載之固形製劑，其中多層錠爲二層 錠，第1層含有奧美沙坦酯，第2層含有阿折地平； (5 ) ( 3 )中記載之固形製劑，其中多層錠爲三層 200835526 錠，第1層含有奧美沙坦酯，夾著中間層的另一層含有阿折 地平； (6) (3)中記載之固形製劑，其中多層錠爲由內 核與外層構成的有核錠，內核含有奧美沙坦酯，外層含有 阿折地平； (7) (3)中記載之固形製劑，其中多層錠爲由內 核與外層構成的有核錠，內核含有阿折地平，外層含有奧 美沙坦酯； (8 ) ( 6 )或（7 )中記載之固形製劑，其中內核與 外層之間含有中間層； (9) ( 5 )或（8 )中記載之固形製劑，其中中間層 含有賦形劑； (10) ( 9 )中記載之固形製劑，其中賦形劑爲1或2 種以上選自乳糖、結晶纖維素、輕質矽酸酐組成之群； (11) ( 1 )至（1 〇 )中任一項記載之固形製劑，其 係用於治療或預防高血壓症； (1 2 ) —種固形製劑之安定化方法，其中固形製劑含 有奧美沙坦酯及阿折地平； (1 3 ) —種含有奧美沙坦酯及阿折地平之固形製劑 之安定化方法，其特徵在於使用（Ο至（Π )中任一項記 載之固形製劑； (1 4 ) 一種奧美沙坦酯之安定化方法，其特徵在於使 用（1 )至（1 1 )中任一項記載之固形製劑等。 發明之效果 -10- 200835526 依據本發明，提供含有奧美沙坦酯及 的固形製劑成爲可能。 【實施方式】 實施發明之最佳形態 本發明之固形製劑之有效成分爲奧美Adipine has been sold as Cal block® (registered trademark) ingots containing 8 mg or 16 mg of the active ingredient adipine, and contains D-mannitol, calcium carboxymethylcellulose as an additive, low degree of substitution. Hydroxypropyl cellulose, sodium hydrogencarbonate, polysorbate 80, magnesium metasilicate aluminate, light phthalic anhydride, hydroxypropyl cellulose, talc, magnesium stearate. In the prior art, the combination of olmesartan medoxomil and adipine is known as the medicine (International Publication No. 2004/067003), but it is not known that the present invention contains the stability of olmesartan medoxomil and adipine Solid preparation. Patent Document 1: Japanese Patent No. 20 825 119 (U.S. Patent No. 5,6,6,5,99) Patent Document 2: Japanese Patent No. 1 6 6 6 7 5 (U.S. Patent No. 4,772, 5 Bulletin No. 96) Patent Document 3: International Publication No. 2004/067003. DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention 200835526 The object of the present invention is to provide a solid preparation containing olmesartan medoxomil and amlodipine, and a method for stabilizing a solid preparation containing olmesartan medoxomil and adipine. In recent years, patients with hypertension have a tendency to use a plurality of agents containing a drug for the treatment of phlegm, which is considered to be a cause of poor blood pressure control. Since the number of doses administered once is reduced, medication compliance is reduced. In order to achieve accurate blood pressure control, it is considered important to improve patient compliance. Omethacillin, an angiotensin II receptor antagonist, and adipine, a calcium channel antagonist, are widely used in medical facilities because they can be expected to have a combination of more effective therapeutic effects of hypertension. The compliance of the medication is improved, and the preparation of the two pharmaceutical agents is strongly expected. In general, when a solid preparation (mixture) containing two types of pharmaceuticals is developed, the prescription of the other active ingredient is often added to one of the single doses. However, in the case of a solid preparation containing olmesartan medoxomil and adipine, the Olmetec8 (registered trademark) ingot or Calblock® (registered trademark) ingot is used as a basis, and olmesartan and/or a The physical or chemical formulation stability of the horizon will deteriorate. This is believed to be due to the unsettled nature of olmesartan medoxomil in the nature of the test, but the abundance of the testin has a stable nature. When the other active ingredient is added to any prescription, the added active ingredient will Become unstable. That is, since the formulation of Calb lock (registered trademark) ingot is alkaline, once omeproxacin is added thereto, olmesartan medoxomil will become unstable. Conversely, because of me 1 metec (registered trademark) ingot The formulation of the preparation is not alkaline. When adding the adipine, the adipine will become not stable in 200835526. Means for Solving the Problems As a result of intensive research to solve the above problems, the present inventors have found that a solid preparation containing olmesartan medoxomil and adipine can be stabilized by separating and dissolving the respective active ingredients without contacting each other. The present invention has been completed. The present invention provides a solid preparation containing olmesartan medoxomil and adipine in a stable form (especially a preparation for prophylaxis or treatment of hypertension), and a preparation for the preparation of the aforementioned solid preparation (especially a preparation for prevention or treatment of hypertension) The use of olmesartan medoxomil and adipine in a pharmacologically effective amount of the aforementioned solid preparation containing olmesartan medoxomil and adipine in the prevention or treatment of diseases in warm-blooded animals (especially humans) (especially Method for the treatment of hypertension, a method for the stabilization of a solid preparation containing olmesartan medoxomil and adipine (in particular, a preparation for prophylaxis or treatment of hypertension). That is, the present invention provides: (1) A solid preparation comprising olmesartan medoxomil and adipine, characterized in that the active ingredients are separated and disposed in such a manner as not to contact each other; (2) the solid form described in (1) The preparation, wherein the solid preparation is in the form of a tablet; (3) The solid preparation described in (2), wherein the tablet is a multi-layer ingot, and olmesartan and adipine are formulated in separate layers; (4) 3) The solid preparation according to 3), wherein the multi-layer ingot is a two-layer ingot, the first layer contains olmesartan medoxomil, the second layer contains adipine; the solid preparation described in (5) (3), wherein the multi-layer ingot is three Layer 200835526 Ingot, the first layer contains olmesartan medoxomil, and the other layer containing the middle layer contains adipine; (6) The solid preparation described in (3), wherein the multi-layer ingot is a core ingot composed of a core and an outer layer. The core contains olmesartan medoxomil and the outer layer contains adipine; (7) The solid preparation described in (3), wherein the multi-layer ingot is a core ingot composed of a core and an outer layer, the core contains abdipine, and the outer layer contains Omega a solid preparation as described in (8) (6) or (7) (9) The solid preparation according to (5) or (8), wherein the intermediate layer contains an excipient; (10) the solid preparation described in (9), wherein the shape is formed The solid preparation according to any one of (1) to (1), which is used for the treatment or prevention, is a solid preparation according to any one of (1) to (1). Hypertensive; (1 2 ) - a method for stabilizing a solid preparation, wherein the solid preparation contains olmesartan medoxomil and adipine; (1 3 ) a stable preparation containing olmesartan medoxomil and adipine And a method of using the solid preparation according to any one of (1); (1) a method for stabilizing olmesartan medoxomil, characterized by using (1) to (1 1 ) A solid preparation according to the invention. Effect of the invention-10-200835526 According to the present invention, it is possible to provide a solid preparation containing olmesartan medoxomil. [Embodiment] The best form for carrying out the invention The active ingredient of the solid preparation of the present invention Ogilvy
ZjS 〇 本發明之固形製劑中有效成分之一的 據日本專利第2 0 8 2 5 1 9號公報（美國專利 報）等記載之方法而容易地製造。 本發明之固形製劑中有效成分之一者 據日本專利第1 6 6 6 7 5 5號公報（美國專利 報）等記載之方法容易地製造。阿折地平π 此等酸加成鹽亦包含於本發明。阿折地平 部分，只要可與阿折地平形成酸加成鹽的 限定，作爲如此之酸’可列舉例如鹽酸、養 硫酸、硝酸、磷酸、乙酸、草酸、丙二酸 酸、酒石酸、號拍酸、檸檬酸、甲磺酸、 磺酸、或萘磺酸’較佳爲鹽酸、氫溴酸、 馬酸、酒石酸、檸檬酸、甲磺酸、苯磺酸 或萘磺酸，更佳爲氫溴酸' 檸檬酸、甲磺 甲苯磺酸、或萘磺酸’再更佳爲氫溴酸、 苯磺酸，又更佳爲氫溴酸或甲磺酸’最佳 本發明中所謂「安定的固形製劑」係 中之奧美沙坦酯及/或阿折地平之化學的 阿折地平之安定 沙坦酯與阿折地 奧美沙坦酯可依 第5,616,599號公 的阿折地平可依 第4,772,596號公 丁形成酸加成鹽， 之酸加成鹽之酸 酸者即可未特別 S溴酸、氫碘酸、 、富馬酸、馬來 苯磺酸、對甲苯 硫酸、磷酸、富 、對甲苯磺酸、 酸、苯磺酸、對 甲磺酸、或對甲 爲氫溴酸。 指保持固形製劑 安定性的固形製 -11- 200835526 劑，較佳爲RNH-6270之含量爲低於8.66% (w/w)及/或總 不純物之含量爲低於13.20% (w/w)，更佳爲RNH-6270之 含量低於2.65% (w/w)及/或總不純物之含量爲低於7.35 % (w/w)，再更佳爲RNH-6270之含量爲低於1.59% ( w/w ) 及/或總不純物之含量爲低於5 · 8 9 % ( w/w ) ’最佳爲 RNH-6270之含量低於1 · 1 〇% ( w/w )及/或總不純物之含量 爲低於 3.39% (w/w)。 安定性可使用高速液體色層分析測定。計算來自色層 分析管柱之標準物質的奧美沙坦酯之保持時間與各種類似 物質之保持時間之比的相對保持時間，可由相對保持時間 鑑定類似物質。由各種類似物質之高峰面積與標準物質之 高峰面積之比計算相對主藥之類似物質含量。安定性較佳 爲依4 (TC 7 5 %相對濕度下放置1個月後測定的類似物質之 含量、更佳爲於40°C 75%相對濕度下放置6個月後測定之類 似物質之含量決定。 本發明中所謂「總不純物」係指來自奧美沙坦酯及阿 折地平之類似物質之總和。 本發明中所謂「固形製劑」，可列舉例如錠劑（含舌下 錠、口腔內崩壞錠）、膠囊劑（含軟膠囊、微膠囊）、顆粒 劑、細粒劑、散劑、九劑、舌片劑等，較佳爲錠劑。 本發明中所謂之「多層錠」，係指數種類處方成分分階 段以層狀堆積而壓縮成形，納入同一劑形內之錠劑（積層 錠），較佳爲具有兩主藥以含有不活性的添加劑之中間層分 離的奧美沙坦酯層及阿折地平層之三層所構成的錠劑。再 -12- 200835526 者，奧美沙坦酯層及/或阿折地平層之外側上可有追加之 層。此等追加的層可爲美觀的目的，亦可爲藥劑味遮蔽、 含有其他有效成分之目的。 本發明中所謂之「二層錠」，係指由含有一方有效成分 之第1層與另一方有效成分之第2層所構成之積層銳。 本發明中所謂之「三層錠」，爲含有一方之有效成分的 第1層、含有不活性的添加劑之第2層（中間層）及含有另 一方有效成分之第3層所構成的積層錠。藉由中間層可迴避 藥物間之直接接觸，而提供更安定化的固形製劑。 本發明中所謂之「有核錠」，爲以含有另一方藥物之外 層包覆含有一方之藥物的內核之錠劑，該內核與外層可相 接，又作爲回避藥物間之直接接觸的目的，可設置以高分 子或糖被覆該內核之中間層。 作爲中間層中使用的不活性添加劑，只要與有效成分 不反應之添加劑即可未特別限定，可列舉作爲通常賦形劑 使用之添加劑等。作爲如此之添加劑，可列舉例如乳糖、 乳糖（造粒粉末）、白糖、葡萄糖、甘露糖醇或山梨糖醇等 糖衍生物；玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精等之澱 粉衍生物；結晶纖維素、結晶纖維素與輕質矽酸酐之噴霧 乾燥品等纖維素衍生物；阿拉伯膠；葡聚糖；或三聚葡糖 等有機系賦形劑；或，輕質矽酸酐、合成矽酸鋁、矽酸鈣 或偏矽酸鋁酸鎂等矽酸鹽衍生物；磷酸氫鈣等磷酸鹽；碳 酸鈣等碳酸鹽；或，硫酸鈣等硫酸鹽等之無機系賦形劑， 較佳爲乳糖（造粒粉末）、結晶纖維素與輕質矽酸酐之噴霧 -13· 200835526 乾燥品、D-甘露糖醇、偏矽酸鋁酸鎂、輕質矽酸酐，更佳 爲結晶纖維素與輕質矽酸酐之噴霧乾燥品。又，中間層可 使用潤滑劑。作爲潤滑劑，可列舉例如硬脂酸鎂、硬脂酸 鈣、富馬酸硬脂酸鈉等硬脂酸衍生物；滑石等礦物資源； 蔗糖脂肪酸酯等脂肪酸衍生物，較佳爲硬脂酸鎂。 本發明之固形製劑，又視必要，可含有適宜之藥理學 上容許之賦形劑、潤滑劑、結合劑、崩壞劑、乳化劑、安 定劑、矯味矯臭劑、稀釋劑等添加劑。 作爲使用之「賦形劑」，可列舉例如乳糖、白糖、葡萄 糖、甘露糖醇或山梨糖醇等之糖衍生物；玉米澱粉、馬鈴 薯澱粉、α-澱粉或糊精等之澱粉衍生物·，結晶纖維素等之 纖維素衍生物；阿拉伯膠；葡聚糖；或三聚葡糖等之有機 系賦形劑；或輕質矽酸酐、合成矽酸鋁、矽酸鈣或偏矽酸 鋁酸鎂等之矽酸鹽衍生物；磷酸氫鈣等之磷酸鹽；碳酸鈣 等之碳酸鹽；或硫酸鈣等之硫酸鹽等之無機系賦形劑。 作爲使用之「潤滑劑」，可列舉例如爲硬脂酸；硬脂酸 鈣或硬脂酸鎂等之硬脂酸金屬鹽；滑石；膠狀矽石；蜂蠟 或鯨鱲等之躐類；硼酸；己二酸；硫酸鈉等之硫酸鹽；乙 二醇；富馬酸；苯甲酸鈉；D，L-白胺酸；十二基硫酸鈉或 十二基硫酸鎂等之十二基硫酸鹽；矽酸酐或矽酸水和物等 之矽酸類；或，上述澱粉衍生物。 作爲使用之「結合劑」，可列舉例如爲羥丙基纖維素、 羥丙基甲基纖維素、聚乙烯吡咯啶酮、聚乙二醇 (m a c r 〇 g ο 1 )，或與前述賦形劑相同之化合物。 -14- 200835526 作爲使用之「崩壞劑」，可列舉例如低取代度羥丙基纖 維素、羧甲基纖維素、羧甲基纖維素鈣或內部交聯羧甲基 纖維素鈉等之纖維素衍生物；交聯聚乙烯吡咯啶酮·，或、 羧甲基澱粉或羧甲基澱粉鈉等之經化學修飾的澱粉•纖維 素類。 作爲使用的「乳化劑」，可列舉例如膨土或VEEGUΜ⑧ 等之膠性黏土；氫氧化鎂或氫氧化鋁等之金屬氫氧化物·， 十二基硫酸鈉或硬脂酸鈣等之陰離子界面活性劑；氯化Τ 烷銨等之陽離子界面活性劑；或，聚氧乙烯烷基醚、聚氧 乙烯山梨聚糖脂肪酸酯或蔗糖脂肪酸酯等之非離子界面活 性劑。 作爲使用的「安定劑」可列舉例如對羥苯甲酸甲酯或 對羥苯甲酸丙酯等之對羥苯甲酸酯類；氯丁醇、苄醇或苯 乙醇等之醇類；氯化苄烷銨；苯酚或甲酚等之酚類；硫柳 永；去氫乙酸；或山梨酸等。 作爲使用的「矯味矯臭劑」，可列舉例如糖精鈉或阿 斯巴甜等之甘味料；檸檬酸、蘋果酸或酒石酸等之酸味料 :或薄荷腦、檸檬、或橘子等之香料等。 作爲使用的「稀釋劑」，可列舉例如乳糖、甘露糖醇、 葡萄糖、蔗糖、硫酸鈣、磷酸鈣、羥丙基纖維素、微結晶 性纖維素、水、乙醇、聚乙二醇、丙二醇、甘油、澱粉、 聚乙烯吡咯啶酮、偏矽酸鋁酸鎂或此等之混合物。 本發明中製劑之製造方法可使用Powder Technology and Pharmaceutical Processes ( D. Chulia 等人，Elsevier -15- 200835526ZjS 〇 One of the active ingredients in the solid preparation of the present invention is easily produced by the method described in Japanese Patent No. 2 0 8 25 1 9 (U.S. Patent Application). One of the active ingredients in the solid preparation of the present invention is easily produced by the method described in Japanese Patent No. 1 6 6 6 5 5 (U.S. Patent Application). Adipine π These acid addition salts are also included in the present invention. The adipine fraction may be exemplified by, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, tartaric acid, and acesulfonic acid as long as it can form an acid addition salt with adipine. , citric acid, methanesulfonic acid, sulfonic acid, or naphthalenesulfonic acid 'preferably hydrochloric acid, hydrobromic acid, horse acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid or naphthalenesulfonic acid, more preferably hydrobromine The acid 'citric acid, methanesulfonic acid toluenesulfonic acid, or naphthalenesulfonic acid' is more preferably hydrobromic acid, benzenesulfonic acid, and more preferably hydrobromic acid or methanesulfonic acid 'best in the present invention, the so-called "stable solid form" In the preparations, the olmesartan medoxomil and/or adipine chemistry of adipine and diazepam and dextromethorphan can be obtained according to the 5,616,599 public adipine can be according to No. 4,772,596 The formation of an acid addition salt, the acid addition salt of the acid can be no special S, bromic acid, hydroiodic acid, fumaric acid, maleic acid, p-toluene sulfuric acid, phosphoric acid, rich, p-toluene Acid, acid, benzenesulfonic acid, p-methanesulfonic acid, or p-hydrazine is hydrobromic acid. Refers to the solid form -11-200835526 agent which maintains the stability of the solid preparation, preferably the content of RNH-6270 is less than 8.66% (w/w) and/or the content of total impurities is less than 13.20% (w/w). More preferably, the content of RNH-6270 is less than 2.65% (w/w) and/or the content of total impurities is less than 7.35 % (w/w), and more preferably the content of RNH-6270 is less than 1.59%. ( w / w ) and / or total impurity content is less than 5 · 8 9 % ( w / w ) 'Best RNH-6270 content is less than 1 · 1 〇% (w / w) and / or total The content of impurities is less than 3.39% (w/w). Stability can be determined using high speed liquid chromatography analysis. The relative retention time of the ratio of the retention time of olmesartan medoxomil from the standard material of the chromatography column to the retention time of various similar substances was calculated, and the similar substance was identified by the relative retention time. The content of similar substances in the main drug is calculated from the ratio of the peak area of various similar substances to the peak area of the reference substance. The stability is preferably based on 4 (TC 7 5 % relative humidity, the content of similar substances measured after being placed for 1 month, more preferably after 6 months at 40 ° C 75% relative humidity) In the present invention, the term "total impurities" refers to the sum of similar substances from olmesartan medoxomil and adipine. In the present invention, the "solid preparation" may, for example, be a tablet (including sublingual ingot, oral cavity collapse). A bad ingot), a capsule (including soft capsules, microcapsules), granules, fine granules, powders, nine doses, tongue tablets, etc., preferably a tablet. The so-called "multilayer ingot" in the present invention is an index. The prescription component is compressed and formed in layers in a layered manner, and is incorporated into a tablet (layered ingot) in the same dosage form, preferably an olmesartan medoxoside layer having an intermediate layer separated by an active ingredient containing two main drugs and A tablet consisting of three layers of a flat layer. In addition, there may be additional layers on the outer side of the olmesartan ester layer and/or the adipine layer. These additional layers may be aesthetically pleasing. Purpose, but also for the taste of the drug, including it The purpose of the "two-layer ingot" as used in the present invention means a layered layer composed of a first layer containing one active ingredient and a second layer of the other active ingredient. The ingot is a layered ingot comprising a first layer containing one active ingredient, a second layer containing an inactive additive (intermediate layer), and a third layer containing the other active ingredient. The intermediate layer can avoid the drug. The direct contact between the two provides a more stable solid preparation. The so-called "nuclear ingot" in the present invention is a lozenge coated with a core containing a drug of the other side, and the core and the outer layer are In addition, as an object of avoiding direct contact between drugs, an intermediate layer of the core may be coated with a polymer or a sugar. As an inactive additive used in the intermediate layer, an additive which does not react with the active ingredient may not be particularly The limitation is, for example, an additive used as a usual excipient. Examples of such an additive include lactose, lactose (granulated powder), white sugar, glucose, and sweet. a sugar derivative such as sugar alcohol or sorbitol; a starch derivative such as corn starch, potato starch, α-starch or dextrin; a cellulose derivative such as a spray dried product of crystalline cellulose, crystalline cellulose and light phthalic anhydride; ; gum arabic; dextran; or organic excipients such as meglucan; or phthalic acid derivatives such as light phthalic anhydride, synthetic aluminum citrate, calcium citrate or magnesium bismuth aluminate; A phosphate such as calcium phosphate; a carbonate such as calcium carbonate; or an inorganic excipient such as a sulfate such as calcium sulfate, preferably a lactose (granulated powder), a spray of crystalline cellulose and light phthalic anhydride-13. 200835526 Dry product, D-mannitol, magnesium metasilicate aluminate, light phthalic anhydride, more preferably spray dried product of crystalline cellulose and light phthalic anhydride. Further, a lubricant can be used as the intermediate layer. Examples thereof include stearic acid derivatives such as magnesium stearate, calcium stearate, and sodium fumarate; mineral resources such as talc; and fatty acid derivatives such as sucrose fatty acid esters, preferably magnesium stearate. The solid preparation of the present invention may, if necessary, contain a suitable pharmacologically acceptable additive such as an excipient, a lubricant, a binder, a breaker, an emulsifier, a stabilizer, a flavoring agent, a diluent, and the like. Examples of the "excipient" to be used include a sugar derivative such as lactose, white sugar, glucose, mannitol or sorbitol; and a starch derivative such as corn starch, potato starch, α-starch or dextrin. a cellulose derivative of crystalline cellulose or the like; an acacia gum; a dextran; or an organic excipient such as a trisaccharide; or a light phthalic anhydride, a synthetic aluminum citrate, a calcium citrate or a bismuth citrate An inorganic excipient such as a phthalate derivative such as magnesium; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; or a sulfate such as calcium sulfate. Examples of the "lubricant" to be used include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal vermiculite; beeswax or whales; Adipic acid; sulfate such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; D, L-leucine; dodecyl sulfate such as sodium dodecyl sulfate or dodecyl magnesium sulfate; a tannic acid such as phthalic anhydride or citric acid water; or the above starch derivative. Examples of the "binding agent" to be used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol (macr 〇g ο 1 ), or the aforementioned excipients. The same compound. -14- 200835526 Examples of the "cracking agent" to be used include fibers of low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or internal croscarmellose sodium. A derivative of a chemically modified starch or cellulose such as cross-linked polyvinylpyrrolidone, or carboxymethyl starch or sodium carboxymethyl starch. Examples of the "emulsifier" to be used include colloidal clay such as bentonite or VEEGUΜ8; metal hydroxides such as magnesium hydroxide or aluminum hydroxide, and anionic interfaces such as sodium dodecyl sulfate or calcium stearate. An active agent; a cationic surfactant such as cerium ammonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester. Examples of the "stabilizer" to be used include parabens such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; and benzyl chloride; Ammonium; phenols such as phenol or cresol; thiourea; dehydroacetic acid; or sorbic acid. Examples of the "flavoring and odorizing agent" to be used include a sweetener such as saccharin sodium or aspartame; a sour material such as citric acid, malic acid or tartaric acid; or a flavoring agent such as menthol, lemon or orange. Examples of the "diluent" to be used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, and propylene glycol. Glycerin, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate or a mixture of these. The method of manufacturing the preparation of the present invention can use Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier -15-200835526).
Science Pub. Co (December 1，1993))等刊物中記載之一 般方法製造，並未特別設限。 本發明之多層錠，例如可以本身公知之方法，將含有 效成分之各層直接壓縮成形，或有效成分各自於各層依通 常之濕式顆粒化或乾式顆粒化（壓縮）方法製造，接著， 藉由將各層壓縮成形而製造。 本發明之二層錠，例如可以本身公知之方法，各自將 第1層、第2層藉由使用通常之濕式顆粒化或乾式顆粒化（壓 縮）方法製造，接著，壓縮第1層與第2層，使用通常之二 層錠成形裝置使兩層結合而製造。 又，本發明之二層錠可設置至少1層的膜包衣。 本發明之三層錠，例如可以本身公知之方法，各自將 第1層、第2層（中間層）、第3層藉由使用通常之直接打錠 用顆粒或濕式顆粒化或乾式顆粒化（壓縮）方法製造，接 著，壓縮第1層、第2層、第3層，使用通常之三層錠成形裝 置使各層結合而製造。又，本發明之三層錠可設置至少1 層的膜包衣。 本發明之有核錠，例如可以本身公知之方法作成內核 部之內核錠，接著，使用有核打錠機將該內核錠以外層部 被覆而製造。 又，上述內核錠（內核）可於以外層被覆之前，施予 薄膜包衣。又，上述內核錠可爲1製劑中有1個內核錠，亦 可有複數個。又，本發明之有核錠可設置至少1層之膜包衣。 包衣，例如使用膜包衣裝置進行，作爲膜包衣基劑， -16- 200835526 可列舉例如糖衣基劑、水溶性膜包衣基劑、腸溶性 基劑、緩放性膜包衣基劑等。 作爲糖衣基劑，使用白糖，又，亦可組合選自 沈降碳酸鈣、磷酸鈣、硫酸鈣、明膠、阿拉伯膠、 吡咯啶酮、三聚葡糖等1種或2種以上使用。 作爲水溶性膜包衣基劑，可列舉例如羥丙基纖 羥丙基甲基纖維素、羥乙基纖維素、甲基羥乙基纖 羧甲基纖維素鈉等之纖維素衍生物；聚乙烯醇、聚 聚乙二醇接枝共聚物、聚乙烯醇-丙烯酸-甲基丙烯 共聚物、聚乙烯縮醛二乙胺乙酸酯、胺基烷基甲基 酯共聚物、聚乙烯吡咯啶酮、聚乙二醇等之合成高 三聚葡糖等之多糖類等。 作爲腸溶性膜包衣基劑，可列舉例如羥丙基甲 素酞酸酯、羥丙基甲基纖維素乙酸丁二酸酯、羧甲 纖維素、乙酸酞酸纖維素等之纖維素衍生物；甲基 共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚1 丙烯酸衍生物；蟲膠等之天然物等。 作爲緩放性膜包衣基劑，可列舉例如乙基纖維 纖維素衍生物；胺基烷基甲基丙烯酸酯共聚物RS、 乙酯·甲基丙烯酸甲酯·共聚物乳濁液等之丙烯酸 等。 上述包衣基劑可將其2種以上以適當比例混合 又’更必要時，可含有適宜之藥理學上容許之可塑 形劑、潤滑劑、隱蔽劑、著色劑、防腐劑等之添加 膜包衣 滑石' 聚乙烯 維素、 維素、 乙烯醇-酸甲酯 丙烯酸 分子； 基纖維 基乙基 丙烯酸 勿S等之 素等之 丙烯酸 衍生物 使用。 劑、賦 劑。 -17- 200835526 本發明之固形製劑之有效成分之奧美沙坦酯與阿折地 平之投與量與投與比率，可依個別藥劑之活性、患者之症 狀、年齡、體重4等種種條件變化。其投與量依症狀、年齡 等而不同，經口投與時，視症狀成人每日的奧美沙坦酯 5mg-80mg (較佳爲 10mg-40mg)、阿折地平 8mg-32mg (較 佳爲8mg-16mg)可以一日1至6次（較佳爲一日1次）投與。 又，本發明固形製劑之有效成分之奧美沙坦酯與阿折 地平之投與量之比率亦爲大幅變動，例如奧美沙坦酯與阿 折地平之投與量比率，重量比可爲1 : 5 0至5 0 : 1之範圍內， 較佳爲1 : 5至5 : 1。最佳形態爲含有奧美沙坦酯/阿折地平 爲 20mg/16mg 或 l〇mg/8mg之旋劑。 本發明之固形製劑，例如有效於預防或治療高血壓症 或來自高血壓症之疾病（更具體而言，爲高血壓症、心臓 疾病〔狹心症、心肌梗塞、心率不整、心衰竭或心肥大〕、 腎臓疾病〔糖尿病性腎症、絲球體腎炎或腎硬化症〕或腦 血管性疾病〔腦梗塞或腦出血〕）等。 實施例 以下’以實施例等更詳細説明本發明，但本發明不受 此限定。 (實施例1 ) 使用以下表1所示成分之彼等量，製作混合顆粒1。將 奧美沙坦酯、低取代度羥丙基纖維素、羥丙基纖維素、乳 糖以高速攪拌造粒機（VG-10，Powrex，約2kg規模）混合 5分鐘後’注加純水攪拌3分鐘，造粒。所得造粒物使用篩 -18- 200835526 粉機（screening mill) (Fiore，德壽工作所，裝置 01〇mm 角之孔徑篩）製成顆粒，於入風溫度9 0 °C之流動層乾燥機 (Glatt WST-5，Powrex )中乾燥後，於篩粉機（COMIL 197S，Powrex，裝置（M.143mm之網眼）中整粒，獲得顆粒 1。 以表1所示比例量秤顆粒1、結晶纖維素及硬脂酸鎂，使 用V型混合機混合獲得混合顆粒1。 其次，依以下表2所示成分使用彼等量，製作混合顆粒 2。 各量秤1 : 1 (重量比）之阿折地平與D-甘露糖醇，以高 速攪拌造粒機（亨舍爾攪拌機（Henschel Mixer ) FM-20， 三井三池製作所）混合5分鐘後，使混合物於錘片式粉碎機 (Hammer mill) ( Sample mill KII WG-1，Fuji Paudal)中 粉碎。又，偏矽酸鋁酸鎂、輕質矽酸酐以高速攪拌造粒機 (亨舍爾攪拌機FM20，三井三池製作所）混合後，於此混 合物中注加聚山梨酸酯8 0，獲得聚山梨酸酯8 0吸附粉末。 所得阿折地平粉碎品、聚山梨酸酯80吸附粉末、D-甘露糖 醇、羧甲基纖維素鈣、低取代度羥丙基纖維素、碳酸氫鈉、 輕質矽酸酐於高速攪拌造粒機（VG-10，Powrex，約2kg規 模）中混合，加入羥丙基纖維素之水溶液（固形分濃度6.5 % )於高速攪拌造粒機（VG-10，Powrex)中進行7.5分鐘 造粒。所得練合物以篩粉機（旋風粉碎機（T 〇 r n a d ο M i 11 )， F· J· Stokes Corp·，裝置0 10mm角之孔徑篩）製成顆粒， 於入風溫度90 °C之流動層乾燥機（Glatt WST-5，Powrex ) 中乾燥後，於篩粉機（旋風粉碎機，F. J. Stokes Corp.，裝 置0 1 · 1 4 3 mm之網孔）中將顆粒整粒，獲得顆粒2。顆粒2、 -19- 200835526 偏矽酸鋁酸鎂、輕質矽酸酐、滑石、硬脂酸鎂以表2所示比 例量秤，使用V型混合機（德壽工作所）混合而獲得混合 顆粒2。 接著，以2 6 0 m g混合顆粒2於第1層中的方式充塡調整、 1 2 0 m g混合顆粒1於第2層中的方式充塡調整，於旋轉打錠機 中使用Φ 9.5 mm之杵，以1 · 5噸之壓縮壓成形打錠。所得錠 劑以羥丙基纖維素、氧化鈦、滑石、純水所構成的包衣溶 液（固形分濃度：1 5 % )於泛包衣機中包衣，獲得膜包衣 錠1。 分取1〇〇錠所得錠劑於玻璃瓶（乾燥劑2g同附於瓶中） 中於4 0 °C 7 5 %相對濕度下實施1個月間安定性試驗。安定性 試驗1個月經時品之RNH-62 70量及總不純物量示於表3。 (比較例1 ) 將實施例1所示混合顆粒1及混合顆粒2各自以6 : 1 3之 比例，於V型混合機中混合5分鐘後，投入Φ 9 · 5 mm之臼中， 旋轉打錠機中每杵1 . 5噸之壓縮壓下成形打錠。與實施例1 所示相同施予膜包衣，獲得膜包衣錠2。 分取1 0 〇錠所得錠劑於玻璃瓶（乾燥劑2 g同附於瓶中） 中於4 0 °C 7 5 %相對濕度下實施1個月間安定性試驗。安定性 試驗1個月經時品之RN Η - 6 2 7 0量及總不純物量示於表3。 (實施例2 ) 秤取260mg之實施例1所示混合顆粒2，投入長徑 14.0mm、短徑6.5mm之臼後，D-甘露糖醇於同一臼中積層， 又秤取1 2 0 m g混合顆粒1投入於同一臼內使其積層，於油壓 -20- 200835526 式單發打錠機中每杵1 . 5噸之壓縮壓下打錠三層錠。所得打 錠品如實施例1所示相同施予包衣，獲得膜包衣锭3。 分取1 〇 〇錠所得錠劑於玻璃瓶（乾燥劑2 g同附於瓶中） 中於40 °C 75%相對濕度下實施1個月間安定性試驗。安定性 試驗1個月經時品之RN Η - 6 2 7 0量及總不純物量示於表3。 (實施例3 ) 乳糖（造粒粉末）、結晶纖維素·輕質矽酸酐噴霧乾燥 品、硬脂酸鎂以下表4所示處方，使用V型混合機混合5分 鐘混合，獲得混合顆粒4。以實施例1所示之260 mg混合顆粒 2充塡調整於第1層的方式，l〇〇mg上述混合顆粒4而成的方 式充塡調整，使於第2層積層，又120mg混合顆粒1而成的方 式充塡調整後，於旋轉式打錠機中使用長徑1 5 . Omm、短徑 7.3mm之杵，以2.5噸壓縮壓，將三層錠成形打錠。所得打 錠品以聚乙烯醇（部分皂化）、氧化鈦、滑石、聚乙二醇、 純水構成的包衣溶液（固形分濃度：2 0 % )於泛包衣機中 包衣，獲得膜包衣錠4。 分取100錠所得錠劑於玻璃瓶（乾燥劑2g同附於瓶中） 中於40°C 75%相對濕度下實施1個月間安定性試驗。安定性 試驗1個月經時品之RN Η - 6 2 7 0量及總不純物量示於表3。 (實施例4 ) 乳糖（造粒粉末）、結晶纖維素·輕質矽酸酐噴霧乾燥 品、偏矽酸鋁酸鎂、輕質矽酸酐、硬脂酸鎂以下表4所示處 方，使用V型混合機混合5分鐘，獲得混合顆粒5。與實施 例3所不相同，於第2層使用混合顆粒5，製作三層淀，使用 -21 - 200835526 實施例3所示包衣溶液（固形分濃度：20% )獲得膜包衣錠 5 ° 分取100錠所得錠劑於玻璃瓶（乾燥劑2§同附於瓶中） 中於4 0 °C 7 5 %相對濕度下實施1個月間安定性試驗。安定性 試驗1個月經時品之RNH-62 70量及總不純物量示於表3。 (試驗例） 使用高速液體色層分析進行試驗。計算來自色層分析 管柱之標準物質的奧美沙坦酯之保持時間與各種類似物質 之保持時間之比的相對保持時間，可由相對保持時間鑑定 類似物質。由各種類似物質之高峰面積及標準物質之高峰 面積之比計算相對於主藥之類似物質含量。 -22- 200835526 〔表1〕 成份 含量（重量份） 奧美沙坦酯 20 低取代度羥丙基纖維素 20 乳糖 66 . 6 羥丙基纖維素 2 . 5 顆粒1 109.1 結晶纖維素 10 硬脂酸鎂 0 . 9 混合顆粒1 合計（mg) 120 〔表2〕 工程品名 成份 含量（重量份） 阿折地平 阿折地平 16 粉碎品 D -甘露糖醇 16 聚山梨酸酯 聚山梨酸酯8 0 40 80吸附粉末 偏矽酸鋁酸鎂 78 輕質矽酸酐 20 D -甘露糖醇 3 低取代度羥丙基纖維素 28 顆粒內成分 羧甲基纖維素鈣 15 碳酸氫鈉 12 輕質矽酸酐 2 羥丙基纖維素 12 顆粒2 242 偏矽酸鋁酸鎂 10 顆粒外成分 輕質矽酸酐 2 滑石 2 硬脂酸鎂 4 混合顆粒2 合計（mg) 260 -23- 200835526 〔表3〕 類似物質名 二層錠 三層錠 三層淀 三層錠 單層錠 膜包衣錠 1 膜包衣錠 3 膜包衣錠 4 膜包衣錠 5 膜包衣錠 2 實施例1 實施例2 實施例3 實施例4 比較例1 RNH-6270 (% ) 0.64 1.10 0.60 0.93 8.66 總不純物 (% ) 2.01 3.39 1.80 2.26 13.20 如表3所示，本發明之固形製劑中奧美沙坦酯之類似物 質（RNH-6 2 70 )之含量及總不純物量與單層錠相比爲低値 化學安定性爲優異。 〔表4〕 實施例 實施例2 實施例3 實施例4 混合顆粒 混合顆粒3 混合顆粒4 混合顆粒5 成份 含量（重量份） 含量（重量份） 含量（重量份） D-甘露糖醇 50 — _ 乳糖（造粒粉末） — 79 74 結晶纖維素·輕質矽酸酐 — 20 20 噴霧乾燥品 偏矽酸鋁酸鎂 — — 4 輕質矽酸酐 — — 1 硬脂酸鎂 — 1 1 合計（mg) 50 100 100 -24- 200835526 産業上之可利用性 依據本發明可獲得含有奧美沙坦酯及阿折地平之安定 的固形製劑。 【圖式簡單說明】 Μ 〇 【主要元件符號說明】 te 〇 j \ \\ -25-One of the methods described in Science Pub. Co (December 1, 1993)) is not specifically limited. The multilayer ingot of the present invention can be directly compression-molded, for example, by a method known per se, or each of the active ingredients can be produced in each layer by a usual wet granulation or dry granulation (compression) method, and then, by Each layer was produced by compression molding. The two-layer ingot of the present invention can be produced, for example, by a method known per se, by using a usual wet granulation or dry granulation (compression) method, and then compressing the first layer and the first layer. Two layers were produced by combining two layers using a conventional two-layer ingot forming apparatus. Further, the two-layer ingot of the present invention may be provided with at least one film coating. The three-layer ingot of the present invention can be used, for example, by a method known per se, by using the usual direct ingot granules or wet granulation or dry granulation by using the first layer, the second layer (intermediate layer) and the third layer. The (compression) method is produced, and then the first layer, the second layer, and the third layer are compressed, and each layer is produced by bonding using a usual three-layer ingot forming apparatus. Further, the three-layer ingot of the present invention may be provided with at least one film coating. The core ingot of the present invention can be produced, for example, by forming a core ingot of a core portion by a method known per se, and then coating the core ingot with a core ingot machine. Further, the core ingot (core) may be coated with a film before being coated on the outer layer. Further, the above-mentioned core ingot may have one core ingot in one preparation, or may have plural ones. Further, the core ingot of the present invention may be provided with at least one film coating. The coating is carried out, for example, using a film coating device, and as a film coating base, for example, a sugar-based base, a water-soluble film coating base, an enteric base, and a slow release film coating base can be cited. Wait. The sugar-based base may be used in combination with one or more selected from the group consisting of precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, pyrrolidone, and trimeric glucose. Examples of the water-soluble film coating base include cellulose derivatives such as hydroxypropylcellulose hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose carboxymethylcellulose; Vinyl alcohol, polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methacryl copolymer, polyvinyl acetal diethylamine acetate, aminoalkyl methyl ester copolymer, polyvinylpyrrolidine A polysaccharide such as a ketone or polyethylene glycol which is synthesized by a high trisaccharide or the like. Examples of the enteric film coating base include cellulose derivatives such as hydroxypropylmethyl phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, and cellulose acetate phthalate. a methyl copolymer L, a methacrylic acid copolymer LD, a methacrylic acid copolymerized acrylic acid derivative, a natural product such as shellac or the like. Examples of the slow release film coating base include an ethyl cellulose derivative, an amino group alkyl methacrylate copolymer RS, an ethyl ester, a methyl methacrylate copolymer emulsion, and the like. Wait. The above-mentioned coating base may be prepared by mixing two or more kinds thereof in an appropriate ratio and, if necessary, containing a suitable pharmacologically acceptable plasticizer, lubricant, concealing agent, coloring agent, preservative, etc. Yixiu 'polyethylene vegan, vitamins, vinyl alcohol-acid methyl acrylate molecules; based on acrylic acid derivatives such as ketone-based ethene acrylate. Agent, agent. -17- 200835526 The administration amount and administration ratio of olmesartan medoxomil and adipine in an active ingredient of the solid preparation of the present invention may vary depending on the activity of the individual agent, the symptoms of the patient, age, and body weight 4. The dosage varies depending on the symptoms, age, etc., and when administered orally, the daily dosage of olmesartan medoxomil 5 mg-80 mg (preferably 10 mg-40 mg) and adipine flat 8 mg-32 mg (preferably 8mg-16mg) can be administered from 1 to 6 times a day (preferably once a day). Moreover, the ratio of the dosage of the olmesartan medoxomil and the adipine in the active ingredient of the solid preparation of the present invention is also greatly changed, for example, the ratio of the administration ratio of olmesartan medoxomil to adipine is 1 : In the range of 5 0 to 5 0 : 1, preferably 1: 5 to 5: 1. The most preferred form is a rotatory agent containing olmesartan medoxomil/ adipine is 20 mg/16 mg or l〇mg/8 mg. The solid preparation of the present invention is, for example, effective for preventing or treating hypertension or a disease derived from hypertension (more specifically, hypertension, palpitations, angina, myocardial infarction, arrhythmia, heart failure or heart) Hypertrophy], renal pelvic disease [diabetic nephropathy, spheroid nephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]). EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited thereto. (Example 1) Mixed particles 1 were produced using the same amounts of the components shown in Table 1 below. The olmesartan medoxomil, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose were mixed by a high-speed stirring granulator (VG-10, Powrex, about 2 kg scale) for 5 minutes. Minutes, granulation. The obtained granules were granulated using a sieve -18-200835526 screening mill (Fiore, Deshou Works, a 0.1 〇mm angle aperture sieve), and a flow layer dryer at a inlet air temperature of 90 °C. After drying in (Glatt WST-5, Powrex), it was granulated in a sieving machine (COMIL 197S, Powrex, apparatus (mesh of M. 143 mm) to obtain granules 1. The granules were weighed in the proportions shown in Table 1. The crystalline cellulose and magnesium stearate were mixed using a V-type mixer to obtain mixed particles 1. Next, the same amount was used for the components shown in the following Table 2 to prepare mixed particles 2. Each weighing scale 1: 1 (weight ratio) Adipine and D-mannitol were mixed in a high-speed stirring granulator (Henschel Mixer FM-20, Mitsui Miike Co., Ltd.) for 5 minutes, and then the mixture was applied to a Hammer mill. (Plastic mill KII WG-1, Fuji Paudal) pulverized. Further, magnesium metasilicate magnesium silicate and light phthalic anhydride were mixed by a high-speed stirring granulator (Henschel mixer FM20, Mitsui Miike Seisakusho Co., Ltd.) Adding polysorbate 80 in the middle to obtain polysorbate 80 adsorption powder The obtained adipine pulverized product, polysorbate 80 adsorption powder, D-mannitol, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, sodium hydrogencarbonate, light phthalic anhydride are stirred at high speed. A granulator (VG-10, Powrex, about 2 kg scale) was mixed, and an aqueous solution of hydroxypropylcellulose (solid concentration: 6.5%) was added to a high-speed stirring granulator (VG-10, Powrex) for 7.5 minutes of granulation. The obtained scouring compound was granulated by a sieving machine (T 〇rnad ο M i 11 , F· J· Stokes Corp., a 0 10 mm aperture sieve), and the inlet air temperature was 90 ° C. After drying in a fluidized bed dryer (Glatt WST-5, Powrex), the granules were granulated in a sifter (cyclone pulverizer, FJ Stokes Corp., mesh of 0 1 · 1 4 3 mm). Granules 2. Granules 2, -19- 200835526 Magnesium metasilicate magnesium aluminate, light phthalic anhydride, talc, magnesium stearate were weighed in the proportions shown in Table 2, mixed using a V-type mixer (Deshou Works) The mixed granules 2 were obtained. Next, the 260 mg of the mixed granules 2 in the first layer was adjusted, 1 2 0 mg The pellets 1 were adjusted in the manner of the second layer, and the ingot was formed by a compression pressure of 1.5 ton using a Φ 9.5 mm crucible in a rotary tableting machine. The obtained tablet was oxidized with hydroxypropylcellulose. A coating solution (solid content concentration: 15%) composed of titanium, talc, and pure water was coated in a pan coater to obtain a film coated ingot 1. The tablet obtained by dispensing one ounce of the ingot was subjected to a one-month stability test at 40 ° C 7 5 % relative humidity in a glass bottle (2 g of the desiccant was attached to the bottle). Stability The amount of RNH-62 70 and the total amount of impurities in the 1 month menstrual test are shown in Table 3. (Comparative Example 1) The mixed particles 1 and the mixed particles 2 shown in Example 1 were each mixed in a V-type mixer at a ratio of 6:1 for 5 minutes, and then placed in a crucible of Φ 9 · 5 mm, and rotated. Ingots were formed into compression ingots at a compression pressure of 1.5 tons per spindle. The film coating was applied in the same manner as in Example 1 to obtain a film coating ingot 2. The tablet obtained by fractionation of 10 ingots was subjected to a one-month stability test at 40 ° C 7 5 % relative humidity in a glass bottle (2 g of desiccant attached to the bottle). Stability The amount of RN Η - 6 27 7 and the total amount of impurities in the 1 month menstrual test are shown in Table 3. (Example 2) 260 mg of the mixed granule 2 shown in Example 1 was weighed, and a long diameter of 14.0 mm and a short diameter of 6.5 mm were placed, and D-mannitol was laminated in the same crucible, and 1 2 0 mg was weighed. The mixed granules 1 were placed in the same crucible to be laminated, and the ingots were ingots under a compression pressure of 1.5 ton per liter in a hydraulic press -20-200835526 single-stranding machine. The obtained ingot was applied in the same manner as in Example 1 to obtain a film coated ingot 3. The tablets obtained by dispensing 1 〇 〇 ingots were subjected to a one-month stability test at 40 ° C and 75% relative humidity in a glass bottle (with 2 g of desiccant attached to the bottle). Stability The amount of RN Η - 6 27 7 and the total amount of impurities in the 1 month menstrual test are shown in Table 3. (Example 3) Lactose (granulated powder), crystalline cellulose, light phthalic anhydride spray-dried product, and magnesium stearate were prepared as shown in Table 4 below, and mixed by a V-type mixer for 5 minutes to obtain mixed particles 4. The method of adjusting the 260 mg of the mixed granules 2 shown in the first embodiment to the first layer, and adjusting the granules of the above-mentioned mixed granules 4 to adjust the granules to form the second layer and 120 mg of the mixed granules After the adjustment method is completed, the three-layer ingot is formed into a spindle by using a long diameter of 1.5 mM and a short diameter of 7.3 mm in a rotary tableting machine at a compression pressure of 2.5 tons. The obtained ingot was coated with a coating solution (solid content concentration: 20%) composed of polyvinyl alcohol (partially saponified), titanium oxide, talc, polyethylene glycol, pure water in a pan coater to obtain a film. Coated ingot 4. The obtained lozenge of 100 ingots was subjected to a one-month stability test at 40 ° C and 75% relative humidity in a glass bottle (drying agent 2 g was attached to the bottle). Stability The amount of RN Η - 6 27 7 and the total amount of impurities in the 1 month menstrual test are shown in Table 3. (Example 4) Lactose (granulated powder), crystalline cellulose, light phthalic anhydride spray-dried product, magnesium metasilicate aluminate, light phthalic anhydride, magnesium stearate, as shown in Table 4 below, using V type The mixer was mixed for 5 minutes to obtain mixed particles 5. Unlike the third embodiment, the mixed particles 5 were used in the second layer to prepare a three-layer lake, and the film coating ingot 5 ° was obtained using the coating solution (solid content concentration: 20%) of Example 3 - 200835526. The obtained lozenge of 100 ingots was subjected to a one-month stability test at 40 ° C 7 5 % relative humidity in a glass bottle (desiccant 2 § attached to the bottle). Stability The amount of RNH-62 70 and the total amount of impurities in the 1 month menstrual test are shown in Table 3. (Test Example) The test was carried out using high-speed liquid chromatography. The relative retention time of the ratio of the retention time of olmesartan medoxomil from the standard material of the chromatography column to the retention time of various similar substances was calculated, and the similar substance was identified by the relative retention time. The content of similar substances relative to the main drug is calculated from the ratio of the peak area of various similar substances and the peak area of the reference substance. -22- 200835526 [Table 1] Ingredient content (parts by weight) Olmesartan Medoxomil 20 Low-substituted hydroxypropylcellulose 20 Lactose 66. 6 Hydroxypropylcellulose 2. 5 Granules 1 109.1 Crystalline cellulose 10 Stearic acid Magnesium 0.9 mixed granules 1 Total (mg) 120 [Table 2] Engineering name Ingredient content (parts by weight) adidipine adipine flat 16 pulverized D-mannitol 16 polysorbate polysorbate 8 0 40 80 adsorption powder magnesium bismuth aluminate 78 light phthalic anhydride 20 D - mannitol 3 low degree of substitution hydroxypropyl cellulose 28 intragranular component carboxymethyl cellulose calcium 15 sodium bicarbonate 12 light phthalic anhydride 2 hydroxy Propyl cellulose 12 granules 2 242 Magnesium metasilicate magnesium aluminate 10 Particulate components Light phthalic anhydride 2 Talc 2 Magnesium stearate 4 Mixed granules 2 Total (mg) 260 -23- 200835526 [Table 3] Similar substance name II Ingot three-layer ingot three-layer three-layer ingot single-layer ingot coating ingot 1 film coating ingot 3 film coating ingot 4 film coating ingot 5 film coating ingot 2 Example 1 Example 2 Example 3 Example 4 Comparative Example 1 RNH-6270 (%) 0.64 1.10 0.60 0.9 3 8.66 Total impurities (%) 2.01 3.39 1.80 2.26 13.20 As shown in Table 3, the content of olmesartan medoxomil (RNH-6 2 70) and the total amount of impurities in the solid preparation of the present invention are compared with the single layer ingot. It is excellent for low chemical stability. [Table 4] EXAMPLES Example 2 Example 3 Example 4 Mixed granules mixed granules 3 Mixed granules 4 Mixed granules 5 Ingredient content (parts by weight) Content (parts by weight) Content (parts by weight) D-mannitol 50 — _ Lactose (granulated powder) — 79 74 Crystalline cellulose · Light phthalic anhydride — 20 20 Spray-dried magnesium bismuth aluminate — 4 Light phthalic anhydride — 1 Magnesium stearate — 1 1 Total (mg) 50 100 100 -24- 200835526 INDUSTRIAL APPLICABILITY According to the present invention, a solid preparation containing olmesartan medoxomil and adipine in a stable form can be obtained. [Simple description of the diagram] Μ 〇 [Description of main component symbols] te 〇 j \ \\ -25-