TWI361070B - Novel pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative - Google Patents
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1361070 九、發明說明： 本案係2003年9月19日所申請之美國專利申請案序 號10/664,803之部分連續案，亦為2002年9月20日申請 之美國專利申請案序號60/412,180與60/412，181之臨時申 請案。 【發明所屬之技術領域】 本發明係關於一種醫藥劑型，其包括抗高血糖 籲 （antihyperglycemic)藥物，與噻唑啶二酮衍生物 (thiazolidinedione derivative)之組合。更具體地，本發明係 關於一種口服劑型’包括雙胍類（biguanide)例如二甲雙胍 (metformin)或丁基雙胍（buformin)或其醫藥可接受之鹽類 - 如二甲雙胍鹽酸鹽或詳述於美國專利第3,957,853及 4,〇80,472號之二曱雙胍鹽類，此處以參考文獻合併於本 文’與嗟唾啶二酮衍生物之組合該嘆唑咬二酮衍生物係 詳述於美國專利第4,687,777號，此處亦以參考文獻合併於. 本文。 【先前技術】 許多技術已用於提供控制釋放及緩釋之醫藥劑型 (dosage f〇rm)以維持藥物之治療性血清濃度並減少因病人 服從性不足所致之未服用藥物後果。 例如’已知緩釋錢劑具有滲透壓活性之藥物核心’外 圍為半通透膜。這類錠劑藉由使水性成分之液體（例如胃或 1361070 腸液）穿透包覆.膜且溶解活性成分，使得所得之藥物溶液可 透過包覆膜通路（passageway)釋出而作用。或者若該活性 成分不溶於滲透液，其可藉由膨服劑handing agent)如水 凝膠經由通路將其推卜這類渗錢㈣統的代表性實例 可見於美國專利第 3,845,77〇、3,916,899、4 〇34 758、 4,077’407、以及4,783,337號。美國專利3 952 741號說明 -種滲透性裝置’纟中活性藥劑只在膜内達到足夠爆炸或 破壞膜t脆弱部分之壓力後自由半通透媒包圍之核心釋 出。 上述專利中該基本的滲透性裝置業已經進一步努力以 .獲得對活性成分釋出的更佳控制。例如，美國專利第 4,777,049以及4,85 1，229號描述一種滲透劑型，其包括一 種圍繞核心之半通壁。該核心含有活性成分與調節劑其 中，該調節劑可使活性成分以脈衝方式穿過半通透膜通路 而釋出。進一步的調整包括修正圍繞該活性核心之半通透 φ膜，例如改變形成該外膜之成份的比例，例如美國專利第 5，178,867、4,587，117以及4,522,625冑，或者增加圍繞該 活性核心之包衣數，如美國專利第5 65〇17〇以及4,892 739 號。 某些採用抗高血糖藥物如二曱雙胍鹽酸鹽之控制釋放 與持續釋放配方已受限於使用膨脹劑或凝膠劑（geUing agent)來控制藥物自劑型之釋出。此經限制之研究說明於 WO 96/08243 之教示以及購自 Brist〇卜Myers Squibb c〇 的。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 /412,181 Temporary application. TECHNICAL FIELD OF THE INVENTION The present invention relates to a pharmaceutical dosage form comprising an antihyperglycemic drug in combination with a thiazolidinedione derivative. More specifically, the present invention relates to an oral dosage form 'including a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or as detailed in the U.S. patent. No. 3, 957, 853 and 4, bis 80, 472, bis-indole salts, which are incorporated herein by reference in its entirety to the combination of the succinyldione derivatives. The azole-dione derivatives are described in detail in U.S. Patent No. 4,687,777. This article is also incorporated herein by reference. [Prior Art] A number of techniques have been used to provide controlled release and sustained release dosage f〇rm to maintain therapeutic serum concentrations of the drug and to reduce the consequences of unmedicated medication due to inadequate patient compliance. For example, the drug core of the known sustained release agent having osmotic pressure activity is surrounded by a semi-permeable membrane. Such a tablet acts by allowing a liquid of an aqueous component (e.g., stomach or 1361070 intestinal fluid) to penetrate the film and dissolve the active ingredient, so that the resulting drug solution can be released through the passage of the coating membrane. Or if the active ingredient is insoluble in the permeate, it can be referred to by a waving agent such as a hydrogel via a vial. A representative example of such a percolation can be found in U.S. Patent Nos. 3,845,77, 3,916,899. 4 〇 34 758, 4,077'407, and 4,783,337. U.S. Patent No. 3,952,741, the disclosure of which is incorporated herein by reference in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all all The basic osmotic device of the above patents has further efforts to obtain better control of the release of active ingredients. For example, U.S. Patent No. 4,777,049 and U.S. Patent No. 4,85,229, the disclosure of each entire entire entire entire entire entire The core contains an active ingredient and a conditioning agent which allows the active ingredient to be pulsating through the semi-permeable membrane passage. Further adjustments include modifying the semi-permeable φ film surrounding the active core, for example, changing the proportion of components forming the outer film, such as U.S. Patent Nos. 5,178,867, 4,587,117, and 4,522,625, or adding a package surrounding the active core. The number of garments, such as U.S. Patent Nos. 5,65,17 and 4,892,739. Certain controlled release and sustained release formulations employing antihyperglycemic agents such as diterpene dihydrochloride hydrochloride have been limited to the use of bulking agents or geUing agents to control the release of the drug from the dosage form. This limited study is described in the teachings of WO 96/08243 and from Brist〇 Myers Squibb c〇
控制釋放之二曱雙胍鹽酸鹽產品中之GLUCOPHAGEtmXR ⑧ 1361070 . 產品說明。 噻唑啶一酮何生物已詳述於美國專利第々Mm? 號。這類化合物於組合治療中的治療價值已進一步閣述於 美國專利第 5,859，G37、5,952,356、5 965 584 ' 615〇 384 以及6’172’09()號1而’此等專利皆未敘述具有本發明優 點之劑型。 含有抗高血糖藥物與噻唑啶二酮衍生物之組合的醫藥 鲁劑型已於先則技藝中提出。例如’ Ep〇 〇 749 751 (此處以 參考文獻合併於本文）說明一種醫藥組成物，其包括胰島素 增敏劑，其可為噻唑啶二酮化合物，加上其他抗糖尿病藥 物。更具體地，EP〇 0 749 751說明較佳的胰島素增敏劑為 . 吡格列酮（Pioglitizone)，其可與他種抗糖尿病藥物諸如二 甲雙胍、苯乙雙胍（phenformin)或丁基雙胍組合，這些藥物 可進一步與傳統上的賦形劑結合（混合及/或包覆）以提供掩 蓋味道或持續釋放的行為。抗高血糖藥物與嗟峻咬二酮衍 φ 生物組合之其他實例為美國專利第6,011，049號（此處以參 考文獻合併於本文）。此專利說明一種緩釋劑型之單一醫藥 組成物’其.含有°比格列_或糖尿病藥物Rezulin (tr〇Htaz〇ne) 及一曱雙脈’諸如滲透幫浦與皮膚貼布（skin patch)。其他 抗高血糖藥物與嗔唑啶二酮衍生物組合之實例可見於美國 專利第 6,524,621、6,475,521、6,451，342、與 6，153,632 號 及PCT專利申請WO 01/3594與W0 01/3594，此處皆以參 .考文獻合併於本文。 先前技藝中亦已知W0 99/47125與美國專利第 1361070 6,〇99,862號揭示一種二甲雙胍滲透性錠劑，其經一種含抗 间血糖或低血糖藥物之立即釋放包衣予以包覆。 雖然先前技藝已揭示含有抗高血糖化合物與噻唑啶二 酮衍生物二者之醫藥劑量配方，但本發明可提供超過先前 技藝甚多的優點且將說明於後。 本發明之目的係提供一種包括第一種活性藥物的劑 型’其係經調配以提供經控制或持續釋放遞送。第一種活 性藥物較佳為抗向血糖化合物。本發明進一步提供第二種 活|±藥物其較佳為噻唑啶二酮衍生物。此處所述之新穎劑 型提供第—種與第二種活性藥物的遞送使得任一藥物的生 體可用率不受食物的存在而減少。 本發明之另一目的，即提供一種劑型，如同上述包 遞送第種活性藥物，為控制或持續釋放配方的抗高血 2化合物’其中該控制或持續釋放的機制並非由膨脹劑聚 合物所調冑，與以立即釋放之包括售㈣二酮衍生物之第 一種活性藥物之組合。 本發明之再一目的，如同上述，即提供一種劑型，包 遞送第種活性藥物，為控制或持續釋放配方的抗高血 〇物，與以立即釋放之包括嗟唑啶二酮衍生物之第二 ^ ^ &藥物之組合’其係以持續且非脈衝性的方式在8至 4】、時期間提供足夠治療濃度的該抗高血糖藥物給需要 類治療的動物或人類。 本發月之又一目的為提供一種劑型，包括遞送第一種 活杜藥物，為控制或持續釋放配方的抗高血糖化合物 1361070 以立即釋放之包括噻唑啶二酮衍生物之第二種活性藥物之 組合，其係在施用後得到約8至12小時之抗高血糖化合物 的高峰血漿濃度，且在施用後得到約丨至4小時之噻唑啶 一嗣衍生物的高峰血楽_濃度。 本發明之又另一目的為提供一種劑型，包括呈控制或 持續釋放之醫藥核心錠劑之第一種活性藥物，其具有均質 之滲透核心，其中該滲透核心成分可採用一般的錠劑壓縮 技術予以製備。 本發明之又再一目的為提供一種劑型，包括遞送第一 種活性藥物，為控制或持續釋放配方的抗高血糖化合物， 與以立即釋放方式遞送包括嘆唾咬二嗣衍生物之第二種活 性藥物之組合’其係在施用後得到約8至12小時之抗高血 糖化合物的高蜂血漿濃度，且在施用後得到約1至4小時 之噻唑啶二酮衍生物的高峰血漿濃度。 本發明之再一目的為提供一種劑型，包括抗呈控制或 持續釋放成分的高血糖藥物，以及呈立即釋放成分之噻唑 啶二酮衍生物，其中不小於噻唑啶二酮衍生物總量的8 5%， 係在施用45分鐘或以内，由此劑型釋出。 本發明之再又一目的為提供一種常溫狀態下保存 (shelf-stable)的劑型，其包含呈控制或持續釋放成分之抗高 血糖藥物以及呈立即釋放成分之噻唑啶二酮衍生物，其中 與噻唑啶二酮有關之化合物或不純物的總量，在儲存兩年 後不超過0.6%且無超過0.2%之個別相關之化合物或不純 !36l〇7〇 【發明内容】 本發明係關於一種醫藥劑型，其包括第一種活性藥 物，較佳為抗高血糖藥物，與第二種活性藥物，較佳為噻 唾咬二_衍生物之組合。更具體地，本發明係關於一種口 服劑型，其包括第一種活性藥物，包含雙胍類如二甲雙胍 或丁基雙胍或其醫藥上可接受的鹽類如二甲雙胍鹽酸鹽或 一甲雙胍鹽類，與包含噻唑啶二酮衍生物之第二種活性藥 $ 物之組合。 前述目的可藉著包括第一種與第二種活性藥物之劑型 來達成，其中第一種活性藥物係調配成控制釋放的核心， - 較佳為滲透錠劑，可使用或不使用凝膠劑或膨脹劑聚合 物。第二種活性成分可為部分之控制釋放核心，或較佳以 提供立即釋放之第二種活性藥物成分的方式與控制釋放的 核心結合。例如，第二種活性成分可與施用至該核心的外 膜合併，或第二種活性成分可施用於經包覆或未經包覆之 _ 控制釋放核心。 於一具體實施例中’第二種活性藥物，其可為噻唑啶 二_衍生物，於該劑型中係以立即釋放之配方提供，而於 該劑型中抗高血糖成分係以控制釋放之配方提供。該配方 之嘆。坐啶二酮衍生物之立即釋放部分應提供丨至12小時之 尚峰血漿濃度（Peak Plasma levels，Tmax)，較佳為1至4小 時’而該配方之抗高血糖成分的控制釋放部分可提供8至 12小時之高峰血漿濃度（Tmax)。 根據本發明該劑型較佳為每天施用一次，較佳為用餐 1361070 •時或用餐後’更加為晚餐時或晚餐後。本發明之劑型於施 支可&供8至12小時之該技高血糖藥物之高峰血漿濃度 (Tmax)亦即提供一整曰之該高峰血漿濃度為治療濃度。 【實施方式】 本主題發明係與一種醫藥配方或劑型有關，其包括含 有抗高血糖藥物之第一種活性藥物與含有噻唑啶二酮衍生 φ 物之第二種活性藥物之組合。抗高血糖藥物較佳為雙胍類 如二甲雙胍或丁基雙胍或其醫藥上可接受的鹽類藥物。抗 尚血糖藥物由錠劑核心以控釋之方式遞送，較佳為具有或 不具有凝膠劑或膨脹劑之滲透錠劑核心。該錠劑核心應包 括抗高血糖藥物及至少一種醫藥上可接受的賦型劑。於本 發明之一具體實施例中，該錠劑核心包括抗高血糖藥物、 結合劑以及吸收增強劑（adsorpti〇n enhancers)，且該鍵劑枝 心較佳為以聚合物包衣包覆俾形成外膜圍繞之錠劑且經過 φ 鑽通以在外膜兩側形成通路。第二種活性藥物包括嗔唾咬 二酮衍生物’較佳為應用在錠劑核心的外膜上而提供立即 釋放或控制釋放之嘆唾咬二酮衍生物。 本說明書中使用之抗高血糖一詞係指可用來控制或管 理非胰島素依賴型糖尿病（NIDDM)之藥物。抗高血糖藥物 包括雙胍類如二甲雙胍、苯乙雙胍或丁基雙胍等，以及其 醫藥上可接受的鹽類、異構體或衍生物。 本說明書中使用之噻唑啶二酮衍生物一詞係指可用來 .控制或管理NIDDM之藥物。這些藥物包括，但不受限於， 11 1361070 胰島素增敏劑（TrogHtazone)、羅格列酮（rosiglitaz〇ne)、吡 格列嗣（pioglitazone)、環格列飼（cigiitazone)等，以及并醫 藥上可接受的鹽類、異構體或衍生物。 結合劑係指任何傳統上已知的醫藥上可接受之結合 劑，諸如聚乙烯吡咯啶酮（p〇lyvinyl pyrr〇lid〇ne)、羥丙基 纖維素、羥乙基纖維素、羥丙基曱基纖維素、乙基纖維素、 聚曱基丙烯酸酯、聚乙烯醇、蠟等。亦可使用前述結合劑 之混合物。較佳的結合劑為水溶性材料如具平均分子量為 25，000至3，000,000之聚乙稀u比洛咬嗣。結合劑可佔該核心 總重之約0%至約40%，較佳約佔該核心總重之約3%至約 1 5%。於一具體實施例中，該核心申之結合劑的使用為選 .擇性的。 於一較佳具體實施例中，該核心可選擇性地包括吸收 增強劑。該吸收增強劑可為此技藝中常見之任何形式的吸 收增強劑例如脂肪酸、界面活性劑（陰離子、陽離子、兩性 • 的）、螯合劑、膽鹽或其混合物。某些較佳的吸收增強劑之 貫例為印填脂；脂肪酸如癸酸（Capric acid)、油酸（〇ieic acid) 及其單甘酯（Monoglyceride);界面活性劑如十二院硫酸納 (Sodium lauryl sulfate)、牛磺膽酸鈉（s〇diuni taurocholate) 及聚山梨醇酯80 (Polysorbate-80);螯合劑如檸檬酸、植 酸、乙二胺四乙酸（EDTA)及乙二醇-雙·（冷·胺基乙基 驗）N，N，N’-四乙酸（EGTA)。以該核心之總重為基準，該核 心可包括約0至約20%之吸收增強劑，最佳為佔核心總重 之約2%至約10%。 12 1361070 於本發明之不採用凝膠劑或膨脹劑聚合物的實施例 中，本發明之核心較佳由抗高血糖藥物加上結合劑形成粒 狀，並壓縮這些顆粒，加入潤滑劑與吸收増強劑以形成錠 劑。該核心亦可藉由將核心成分通過乾式造粒機（r〇Uer compactor)進行乾燥造粒’並於錠劑中加入潤滑劑而壓縮這 些顆粒而形成該核心。直接壓縮亦可用來製錠。其他一般 造粒步驟係屬習知。而且，其他賦型劑如潤滑劑、色素或 染劑亦可用於本發明的製劑過程。 凝膠劑或膨脹劑聚合物係指於水或生物液體存在時可 膠化、膨脹或展延的聚合物》凝膠劑或膨脹劑聚合物的代 表性實例為高分子量的經丙基甲基纖維素（如 METHOCEL® K100M，購自 Dow Chemical 公司）以及高分 子量的聚環氧乙烧類（如POLYOX WSR 301，WSR 303或 WSR COAGULANT)。其他凝膠劑或膨脹劑聚合物係詳述於 美國專利第4,522,625號（此處以參考文獻合併於本文）。 此處敘述所形成的核心，可覆以外膜或持續釋放之包 衣。用於形成外膜或持續釋放包衣的材料為乙基纖維素、 纖維酯類、纖維素二酯類、纖維素三酯類、纖維素醚類、 纖維素醚-醋、纖維素酿醋（cellul〇se aCylate)、纖維素二酿 酯（cellulose diacylate)、纖維素三醢酯（cellulose triacylate)、纖維素醋酸酯、纖維素二醋酸酯、纖維素三醋 酸醋、醋酸丙酸纖維素（cellulose, acetate propionate)以及醋 酸丁酸纖維素（cellulose acetate butyrate) »其他合適的聚合 物係詳述於美國專利第3,845,770、3,916,899、4,008,719、 ⑧ 1361070 ' 4,036,228及4，川，008號（此處皆以參考文獻合併於本 文）。最佳的外膜或持續釋放包衣材料為纖維素醋酸酯，其 包括含量為39.3至40.3%之乙酿基，且可構自Eastm^Fin、e Chemicals 公司。 於另一具體實施例中，外膜或持續釋放包衣可包含一 種上述聚合物及増流劑（flux_enhancing agent)。此增流劑可 增加該核心接受液體之體積，以使該劑型實質上可經過通 φ路及7或此多孔膜而分散所有的抗高血糖藥物。增流劑可為 水溶性材料或腸的材料。較可作為增流劑之較佳材料的實 例為氣化鈉、氣化卸、蔗糖、山梨糖醇、甘露糖醇、聚乙 .二醇（PEG)、丙二醇、經丙基纖維素、經丙基甲基纖維素、 . 羥丙基曱基纖維素鄰苯二甲酸酯、纖維素醋酸酯鄰笨二曱 酸酯（cellulose acetate phthaUte)、聚乙烯醇曱基丙烯酸 共聚物、帕洛沙姆（P〇丨oxamer)(如 LUTROL F68、LUTROL F127、LUTROL F108，可購自BASF)及其混合物等。較佳 φ 的增流劑為PEG 400 » 增流劑亦可為水溶性藥物，如二甲雙胍或其醫藥上可 接文之鹽類，或者該增流劑可為在腸内環境下可溶解的藥 物。若增流劑為藥物，本發明之劑型具有提供藥物立即釋 放之附加的優點，該藥物經挑選作為增流劑。 增流劑佔包衣總重之約〇至約4〇%，最佳佔外衣總重 之約2%至約20%。增流劑由外膜或持續釋放包衣開始溶解 或溶遽’而在外膜或持續釋放包衣中形成通道（channels)使 液體進入核心並溶解活性成分。 1361070 • 該外膜或持續釋放包衣亦可利用習知之賦型劑如增塑 劑（plasticizer)來形成。一些習知之增塑劑包含己二酸醋、 壬二酸醋（azelate)、安息香酸醋（benzoate)、棒檬酸酿、硬 脂酸酯（stearate)、愛索布凱（isoebucate)、癸二酸西^ (sebacate)、檸檬酸三乙酯、檸檬酸三正丁酯、乙醯基棒樣 酸三正丁酯（acetyl tri-n-butyl citrate)、檸檬酸酯以及詳述 於JohnWiley & Sons出版的聚合物科學及科技百科全奎 (Encyclopedia of Polymer Science and Technology)第 i〇 卷 ^ 中所列者。較佳之增塑劑為醋酸甘油酯（triacetin)、乙酿化 單甘油酯（acetylated monoglyceride)、葡萄子油、撖欖油、 芝麻油、檸檬酸乙醯基三丁酷、檸檬酸乙醯基三乙醋、甘 油、山梨醇、草酸二乙醋、頻果酸二乙醋、富馬酸二乙酿、 丁二酸二丁酯、丙二酸二乙酯、鄰笨二甲酸二辛酯、癸二 酸二丁醋、檸檬酸三乙酯、檸檬酸三丁酯、三丁酸甘油醋 (glycerol tributyrate)等。根據特定之增塑劑，以外膜或持 _ 續釋放包衣之總重為基準’該增塑劑之含量為約〇至約 25%，較佳為約2%至約15%。 一般而s，該核心周圍之外膜或持續釋放包衣佔核心 與包衣總重之約1 〇/0至約1 〇〇/。，較佳約2%至約5%。 於一較佳具體實施例中，該核心周圍之外膜或持續釋 放包衣可進一步包括通路，該通路可使受控制釋放之藥物 由核心釋出。此處通路一詞包含穿孔（aperture)、開口 (〇rifiCe)、孔（bore)、洞、脆弱區域或沖蝕區，如明膠栓塞 受腐蝕成為滲透通路以由該劑型釋放出抗高血糖藥物。本 15 ⑧ 1361070 發明使用之通路係屬習知者且與詳述於美國專利第 3风770、3,916,899、4，G34,758、4，G77 4G7、4 783 337 及5，07 1，607號者一致。 與抗高血糖藥物無關者係第二種活性藥物，較佳為噻 嗤咬二萌衍生物。此第二種活性藥物可經調配俾提供可立 即釋放之❹$二酮衍生物。於本發明之—具體實施例 中，該㈣咬二酮衍生物係利用結合劑&其他習知之醫藥 賦型劑(例如吸收增強劑、界面活性劑、增塑劑、防泡劑 (antifoaming agents)及前述物質之組合）以層狀形式施用至 含有層狀抗高A糖藥物之控制釋放或持續釋放核心。售咕 咬二酮衍生物層巾錄增強劑的含量可高達約娜咖之 ❹㈣生物重量°結合劑的含量可高達約150% w/w 之噻唑啶二_衍生物重量。第二種活性藥物的立即釋放配 方可藉由傳統方法包覆至該劑型的外膜或持續釋放包衣上 以。併為單一劑型。或者，其亦可經由任何醫藥上可接受 的方法與第一種活性藥物合併成單一劑型。合併第二種活 性藥物的方法可選自下列程序，但不受限於此：如藥物成 層、^層、乾燥麗縮、沉殺（dep〇siu〇n)與印花（prinUng)。 當噻唑啶二酮衍生物經包覆至滲透錠劑核心的外膜或 持續釋放包衣上時’該㈣咬二綱衍生物包衣層應由採用 .水性溶劑、有機溶劑或水性與有機溶劑之混合物的包衣溶 液或懸浮液來進行包覆。典型的有機溶劑包括丙酮、異丙 醇、甲醇及乙醇。若使用水性與有機溶劑之混合物，水與 有機溶劑之比例應由98:2至2:98，較佳為5〇 5〇至Ml ⑧ 16 070 最佳為30:70至20:80以及理想中為約25:75至2〇:8〇。若 使用混合溶劑系統’將嗟唾咬二酮衍生物包覆至該外膜或 持續釋放包衣上時所需之結合劑的份量可以減少。例如， 已自混合溶劑系統得到成功的包衣，其中結合劑對噻唑啶 二嗣衍生物的比例為1:9至1:11。雖然噻唑啶二酮衍生物 包衣可直接施用在外膜或持續釋放包衣上而得到可接受之 包衣’較佳的做法為在施用噻唑啶二酮衍生物包衣前先以 封裝包衣（seal coat)包覆該外膜或持續釋放包衣。封裝包衣 係指不含活性醫藥成分且可迅速分散或溶解在水中的包 衣。 噻唑啶二酮衍生物包衣溶液或懸浮液亦可含有界面活 性劑與成孔劑（pore f0rming agent)。成孔劑較佳為水溶物質 如氣化鈉、氣化鉀、蔗糖、山梨醇、甘露糖醇、聚乙二醇 (PEG)、丙二醇、羥丙基纖維素、羥丙基甲基纖維素、羥丙 基曱基纖維素鄰苯二甲酸酯、纖維素醋酸酯鄰苯二甲酸 酯、聚乙烯醇、甲基丙烯酸共聚物、帕洛沙姆（如 F68、LUTROL F127 與 LUTROL F108，可購自 BASF)及其 混合物等。另一具體實施例中，本發明之劑型亦可包括有 效立即釋放量之抗高血糖藥物。此有效立即釋放量之抗高 血糖藥物，可塗覆該劑型之外膜或持續釋放包衣上，或者， 其可合併於外膜或持續釋放包衣中。 另外’可使用各種揭露於Remington’s PharmaceuticalGLUCOPHAGEtmXR 8 1361070 in the controlled release of diterpene dihydrochloride hydrochloride product. Product description. The thiazolidine-ketone organism has been described in detail in U.S. Patent No. MM. The therapeutic value of such compounds in combination therapy has been further described in U.S. Patent Nos. 5,859, G37, 5,952,356, 5 965 584 '615 384, and 6'172'09 () No. 1 and none of these patents have A dosage form of the advantages of the invention. A pharmaceutical dosage form containing a combination of an antihyperglycemic drug and a thiazolidinedione derivative has been proposed in the prior art. For example, 'Ep〇 749 749 751 (hereby incorporated by reference), which is incorporated herein by reference in its entirety, is incorporated herein by reference in its entirety in its entirety in its entirety in the in the in the More specifically, EP 〇 0 749 751 teaches that a preferred insulin sensitizer is Pioglitizone, which can be combined with other antidiabetic drugs such as metformin, phenformin or butyl biguanide. It is further combined (mixed and/or coated) with conventional excipients to provide a masking or sustained release behavior. Other examples of anti-hyperglycemic agents and scorpion ketone derivatives are disclosed in U.S. Patent No. 6,011,049, the disclosure of which is incorporated herein by reference. This patent describes a single pharmaceutical composition of a sustained release dosage form which contains a ratio of granules or a diabetic drug Rezulin (tr〇Htaz〇ne) and a double vein such as an infiltration pump and a skin patch. . Examples of other antihyperglycemic agents in combination with oxazolidinedione derivatives can be found in U.S. Patent Nos. 6,524,621, 6,475,521, 6,451,342, 6,153,632, and PCT patent applications WO 01/3594 and WO 01/3594, here All of them are incorporated in this article. It is also known in the prior art that WO 99/47125 and U.S. Patent No. 1,361,070, 6, 99, 862 disclose a metformin osmotic tablet coated with an immediate release coating comprising an anti-hyalglycemic or hypoglycemic agent. While the prior art has disclosed pharmaceutical dosage formulations containing both antihyperglycemic compounds and thiazolidinedione derivatives, the present invention provides advantages over the prior art and will be described hereinafter. It is an object of the present invention to provide a dosage form comprising a first active drug which is formulated to provide controlled or sustained release delivery. The first active drug is preferably an anti-glycemic compound. The invention further provides a second live drug, preferably a thiazolidinedione derivative. The novel dosage forms described herein provide delivery of the first and second active agents such that the bioavailability of either drug is reduced by the presence of food. Another object of the present invention is to provide a dosage form which, like the above-described package delivers the first active drug, is a controlled or sustained release formulation of an anti-hyperglycemic 2 compound wherein the mechanism of controlled or sustained release is not modulated by the expander polymer胄, in combination with the first active drug comprising an immediate release of a (d) diketone derivative. A further object of the present invention, as described above, is to provide a dosage form comprising a delivery of a first active agent, an anti-hypertensive substance for controlled or sustained release formulation, and a first release comprising an oxazolidinedione derivative. The combination of the drug and the drug provides a sufficient therapeutic concentration of the antihyperglycemic drug to the animal or human in need of treatment in a continuous and non-pulsating manner at 8 to 4 hours. A further object of the present month is to provide a dosage form comprising the delivery of a first live drug, a controlled or sustained release formulation of an antihyperglycemic compound 1361070 for immediate release of a second active drug comprising a thiazolidinedione derivative A combination of peak plasma concentrations of anti-hyperglycemic compounds of about 8 to 12 hours after administration and a peak blood concentration of thiazolidine-indole derivatives of about 丨 to 4 hours after administration. Still another object of the present invention is to provide a dosage form comprising a first active drug of a controlled or sustained release pharmaceutical core tablet having a homogeneous osmotic core, wherein the osmotic core component can employ a general tablet compression technique Prepared. Still another object of the present invention is to provide a dosage form comprising delivering a first active drug, an anti-hyperglycemic compound for a controlled or sustained release formulation, and a second delivery comprising a sigh bite derivative in an immediate release manner The combination of active drugs' is a high bee plasma concentration of anti-hyperglycemic compounds obtained after administration for about 8 to 12 hours, and a peak plasma concentration of the thiazolidinedione derivative is obtained after administration for about 1 to 4 hours. A further object of the present invention is to provide a dosage form comprising a hyperglycemic drug against a controlled or sustained release component, and a thiazolidinedione derivative in an immediate release component, wherein not less than 8 of the total amount of the thiazolidinedione derivative 5%, applied within 45 minutes or less, whereby the dosage form is released. Still another object of the present invention is to provide a shelf-stable dosage form comprising an antihyperglycemic drug in a controlled or sustained release component and a thiazolidinedione derivative in an immediate release component, wherein The total amount of the compound or impurity related to the thiazolidinedione, not more than 0.6% after storage for two years and no more than 0.2% of the individual related compound or impure! 36l〇7〇 [Abstract] The present invention relates to a pharmaceutical dosage form It comprises a first active drug, preferably an antihyperglycemic drug, in combination with a second active drug, preferably a thiophene di-derivative. More particularly, the present invention relates to an oral dosage form comprising a first active agent comprising a biguanide such as metformin or butyl biguanide or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or mono-biguanide salt, In combination with a second active drug comprising a thiazolidinedione derivative. The foregoing objects can be achieved by a dosage form comprising a first active agent, wherein the first active drug is formulated as a core for controlled release, preferably an osmotic tablet, with or without a gelling agent. Or a swelling agent polymer. The second active ingredient can be part of a controlled release core, or preferably combined with a controlled release core in a manner that provides an immediate release of the second active pharmaceutical ingredient. For example, the second active ingredient can be combined with the outer membrane applied to the core, or the second active ingredient can be applied to the coated or uncoated _ controlled release core. In a specific embodiment, the second active drug, which may be a thiazolidine derivative, is provided in the dosage form in an immediate release formulation, wherein the antihyperglycemic component is in a controlled release formulation. provide. The sigh of this formula. The immediate release portion of the pyridinedione derivative should provide a Peak Plasma level (Tmax) of 12 to 12 hours, preferably 1 to 4 hours' and the controlled release portion of the antihyperglycemic component of the formulation can be A peak plasma concentration (Tmax) of 8 to 12 hours is provided. Preferably, the dosage form according to the invention is applied once a day, preferably at 13,610,70 hours or after the meal, even more for dinner or after dinner. The dosage form of the present invention is administered at a peak plasma concentration (Tmax) of the hyperglycemic drug for 8 to 12 hours, i.e., the peak plasma concentration is provided as a therapeutic concentration. [Embodiment] The subject invention relates to a pharmaceutical formulation or dosage form comprising a combination of a first active drug comprising an antihyperglycemic agent and a second active agent comprising a thiazolidinedione derived φ substance. The antihyperglycemic drug is preferably a biguanide such as metformin or butyl biguanide or a pharmaceutically acceptable salt thereof. The anti-glycemic drug is delivered by controlled release of the tablet core, preferably an infiltrated tablet core with or without a gel or bulking agent. The lozenge core should include an antihyperglycemic agent and at least one pharmaceutically acceptable excipient. In a specific embodiment of the present invention, the tablet core comprises an antihyperglycemic drug, a binding agent, and an absorption enhancer, and the bond center is preferably coated with a polymer coating. A lozenge surrounded by the outer membrane is formed and drilled through φ to form a passageway on both sides of the outer membrane. The second active drug, including the sputum bite diketone derivative, is preferably a snail diketone derivative which is applied to the outer membrane of the tablet core to provide immediate or controlled release. The term antihyperglycemic as used in this specification refers to a drug that can be used to control or manage non-insulin dependent diabetes mellitus (NIDDM). Antihyperglycemic agents include biguanides such as metformin, phenformin or butyl biguanide, and pharmaceutically acceptable salts, isomers or derivatives thereof. The term thiazolidinedione derivative as used in this specification refers to a drug that can be used to control or manage NIDDM. These drugs include, but are not limited to, 11 1361070 insulin sensitizer (TrogHtazone), rosiglitazone (negliglidaz〇ne), pioglitazone (pioglitazone), cigitazone (cigiitazone), etc. An acceptable salt, isomer or derivative. A binder refers to any conventionally known pharmaceutically acceptable binder, such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl. Mercapto cellulose, ethyl cellulose, polydecyl acrylate, polyvinyl alcohol, wax, and the like. Mixtures of the foregoing bonding agents can also be used. Preferred binders are water soluble materials such as polyethylene bromide having an average molecular weight of from 25,000 to 3,000,000. The binder may comprise from about 0% to about 40% by weight of the core, preferably from about 3% to about 5% by weight of the core. In one embodiment, the use of the core binding agent is optional. In a preferred embodiment, the core optionally includes an absorption enhancer. The absorption enhancer can be any form of absorption enhancer commonly known in the art such as fatty acids, surfactants (anionic, cationic, amphoteric), chelating agents, bile salts or mixtures thereof. Some preferred examples of absorption enhancers are printing fats; fatty acids such as capric acid, 〇ieic acid and monoglyceride; surfactants such as sodium sulfoxide (Sodium lauryl sulfate), sodium taurocholate and polysorbate-80; chelating agents such as citric acid, phytic acid, ethylenediaminetetraacetic acid (EDTA) and ethylene glycol - Bi·(cold·aminoethyl) N,N,N′-tetraacetic acid (EGTA). Based on the total weight of the core, the core may comprise from about 0 to about 20% of the absorption enhancer, preferably from about 2% to about 10% by weight of the total core. 12 1361070 In the embodiment of the present invention which does not use a gelling agent or a swelling agent polymer, the core of the present invention is preferably formed into a granular form by an antihyperglycemic drug plus a binding agent, and compresses the particles, adding a lubricant and absorbing. A strong agent to form a tablet. The core may also form the core by dry granulating the core component by a dry granulator and adding a lubricant to the tablet to compress the granules. Direct compression can also be used for ingot making. Other general granulation steps are conventional. Moreover, other excipients such as lubricants, pigments or dyes can also be used in the formulation process of the present invention. Gel or expander polymer refers to a polymer that can be gelled, expanded or stretched in the presence of water or a biological fluid. A representative example of a gel or expander polymer is a high molecular weight propylmethyl group. Cellulose (such as METHOCEL® K100M, available from Dow Chemical) and high molecular weight poly Ethylene bromide (such as POLYOX WSR 301, WSR 303 or WSR COAGULANT). Other gelling or swelling agent polymers are described in detail in U.S. Patent No. 4,522,625, the disclosure of which is incorporated herein by reference. The core formed is described herein and can be coated with an outer film or a sustained release coating. The materials used to form the outer film or the sustained release coating are ethyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ether-vinegar, cellulose vinegar ( Cellul〇se aCylate), cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate , acetate propionate) and cellulose acetate butyrate » Other suitable polymers are described in detail in U.S. Patents 3,845,770, 3,916,899, 4,008,719, 8 1361070 '4,036,228 and 4, Sichuan, 008 (here References are incorporated herein. The most preferred outer film or sustained release coating material is cellulose acetate, which comprises an ethylene acylate in an amount of from 39.3 to 40.3%, and is available from Eastm^Fin, e Chemicals. In another embodiment, the outer film or sustained release coating can comprise a polymer as described above and a flux_enhancing agent. The flow enhancer can increase the volume of the core receiving liquid so that the dosage form can substantially disperse all of the antihyperglycemic agents through the φ pathway and 7 or the porous membrane. The flow enhancer can be a water soluble material or a material of the intestine. Examples of preferred materials that can be used as flow enhancers are sodium gasification, gasification, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, propyl cellulose, and propylene. Methyl cellulose, hydroxypropyl decyl cellulose phthalate, cellulose acetate phthaUte, polyvinyl alcohol methacrylate copolymer, Palosham (P〇丨oxamer) (such as LUTROL F68, LUTROL F127, LUTROL F108, available from BASF) and mixtures thereof. Preferably, the φ flow-enhancing agent is PEG 400 » The flow-increasing agent may also be a water-soluble drug, such as metformin or a pharmaceutically acceptable salt thereof, or the flow-increasing agent may be a drug soluble in the intestinal environment. . If the flow-increasing agent is a drug, the dosage form of the present invention has the added advantage of providing immediate release of the drug, which is selected as a flow-enhancing agent. The flow-increasing agent comprises from about 〇 to about 4% by weight of the total coating, preferably from about 2% to about 20% by weight based on the total weight of the garment. The flow enhancer begins to dissolve or dissolve by the outer membrane or sustained release coating to form channels in the outer membrane or sustained release coating to allow liquid to enter the core and dissolve the active ingredient. 1361070 • The outer film or continuous release coating can also be formed using conventional excipients such as plasticizers. Some conventional plasticizers include adipic acid vinegar, azelate, benzoate, citric acid, stearate, isebucate, and bismuth. Sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citrate and detailed in John Wiley & Sons published in Encyclopedia of Polymer Science and Technology, i. Preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, eucalyptus oil, sesame oil, acetaminophen citrate, citrate triethyl citrate Vinegar, glycerin, sorbitol, oxalic acid, diethyl vinegar, diacetic acid, diethyl fumarate, dibutyl succinate, dibutyl succinate, diethyl malonate, dioctyl phthalate, bismuth Dibutyl vinegar, triethyl citrate, tributyl citrate, glycerol tributyrate, and the like. The plasticizer is present in an amount of from about 〇 to about 25%, preferably from about 2% to about 15%, based on the total weight of the particular plasticizer, the outer film or the continuous release coating. Typically, the outer membrane or sustained release coating around the core comprises from about 1 〇/0 to about 1 〇〇/ of the total weight of the core and coating. Preferably, it is from about 2% to about 5%. In a preferred embodiment, the core surrounding outer membrane or sustained release coating may further comprise a pathway that allows controlled release of the drug to be released from the core. The term pathway herein includes an aperture, an opening (〇rifiCe), a bore, a hole, a fragile area, or an erosion zone, such as a gelatin embolism that is corroded into an infiltration pathway to release an antihyperglycemic drug from the dosage form. The passages used in the present invention are those of the prior art and are described in detail in U.S. Patent Nos. 3, 770, 3, 916, 899, 4, G34, 758, 4, G77 4G7, 4 783 337 and 5, 07 1,607. Consistent. The second active drug is not related to the antihyperglycemic drug, and is preferably a thiophene biting derivative. This second active drug can be formulated to provide a ready-to-release 二$ diketone derivative. In a specific embodiment of the invention, the (d) diced diketone derivative utilizes a binder & other conventional pharmaceutical excipients (eg, absorption enhancers, surfactants, plasticizers, antifoaming agents). And a combination of the foregoing) is applied in a layered form to a controlled release or sustained release core comprising a layered anti-high A sugar drug. The content of the diced diketone derivative layer can be as high as about 5% of the bio-weight. The amount of the binder can be up to about 150% w/w of the weight of the thiazolidine derivative. The immediate release formulation of the second active drug can be applied to the outer film of the dosage form or to the sustained release coating by conventional methods. And a single dosage form. Alternatively, it may be combined with the first active drug in a single dosage form via any pharmaceutically acceptable method. The method of combining the second active drugs may be selected from the following procedures, but is not limited thereto: for example, drug layering, layering, drying, shrinking, dep〇siu〇n, and printing (prinUng). When the thiazolidinedione derivative is coated onto the outer membrane of the core of the osmotic tablet or the sustained release coating, the coating layer of the bismuth derivative should be used. An aqueous solvent, an organic solvent or an aqueous and organic solvent. The coating solution or suspension of the mixture is coated. Typical organic solvents include acetone, isopropanol, methanol and ethanol. If a mixture of aqueous and organic solvents is used, the ratio of water to organic solvent should be from 98:2 to 2:98, preferably from 5〇5〇 to Ml 8 16 070, optimally from 30:70 to 20:80, and ideally It is about 25:75 to 2:8. If a mixed solvent system is used, the amount of the binder required to coat the sputum diketone derivative onto the outer membrane or the sustained release coating can be reduced. For example, a successful coating has been obtained from a mixed solvent system in which the ratio of binding agent to thiazolidinediamine derivative is from 1:9 to 1:11. Although the thiazolidinedione derivative coating can be applied directly to the outer film or to the sustained release coating to provide an acceptable coating, it is preferred to coat the coating prior to application of the thiazolidinedione derivative coating ( The seal coat coats the outer film or continuously releases the coating. Package coating means a coating that does not contain active pharmaceutical ingredients and that can be rapidly dispersed or dissolved in water. The thiazolidinedione derivative coating solution or suspension may also contain a surfactant and a pore f0rming agent. The porogen is preferably a water-soluble substance such as sodium carbonate, potassium carbonate, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Hydroxypropyl decyl cellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymer, Palosam (such as F68, LUTROL F127 and LUTROL F108, Purchased from BASF) and mixtures thereof. In another embodiment, the dosage form of the invention may also comprise an effective immediate release amount of an antihyperglycemic agent. The effective immediate release amount of the anti-hyperglycemic agent can be applied to the outer membrane of the dosage form or to the sustained release coating, or it can be incorporated into the outer membrane or the sustained release coating. In addition, various disclosures can be used in Remington’s Pharmaceutical
Sciences (1995)之稀釋劑、賦型劑、潤滑劑 '染料、色素、 分散劑等，俾用來最;適化上述所列舉之本發明之配方。 1361070 雙胍類，如二甲雙胍經常以500毫克、750毫克、850 毫克、及10 00毫克之劑型投予。噻唑啶二酮衍生物，例如 吡格列酮，則經常以1 5毫克、30毫克及45毫克之劑型投 予。本發明欲包括上述列舉之治療組合，但並不明確提供 化合物之各種可能的組合及其代表劑量之特定實例。 該劑型之較佳具體實施例將具有下列組成：The diluents, excipients, and lubricants of the Sciences (1995) 'dye, coloring matter, dispersing agent, etc., are used to optimize the formulation of the present invention as enumerated above. 1361070 Biguanides, such as metformin, are often administered in dosage forms of 500 mg, 750 mg, 850 mg, and 100 mg. Thiazolidinedione derivatives, such as pioglitazone, are often administered in dosage forms of 15 mg, 30 mg and 45 mg. The present invention is intended to include the above-listed therapeutic combinations, but does not explicitly provide the various possible combinations of the compounds and the specific examples thereof. Preferred embodiments of the dosage form will have the following composition:
第一種活性藥物 核心. 含量(佔核心之°/〇) 藥物 50 至 98 % (較佳為75至95%) 結合劑 0.1 至 40 % (較佳為3至15%) 吸收增強劑 0 至 20 % (較佳為2至10%) 潤滑劑 0至5 % (較佳為〇_5至1%) 外膜： 含量(佔外膜之％) 聚合物 50 至 99 % (較佳為75至95%) 增流劑 0 至 40 % (較佳為2至20%) 增塑劑 0 至 25 % (較佳為2至15%) 第二種活性藥物 含量(佔總劑型之°/〇) 藥物 0.1 至 20 % (較佳為1至10%) 結合劑 0.1 至 30 % (較佳為1至15%) 界面活性劑 0 至 20 % (較佳為0.1至15%) 成孔劑 0 至 25 % (較佳為0.1至15%) 聚合物(視需要） 0 至 30 % (較佳為0.1至20%) 1361070 當以USP Type 2裝置於37°c，75 rpm，900毫升之仿 腸液（pH7.5磷酸鹽緩衝液）中測試時，根據本發明所製備之 劑型可表現出下列溶離基本資料（dissolution profile): 釋出第一種活性藥物 時間(小時） 釋出％ 2 0 至 25 % (較佳為0至15%) 4 10 至 45 v (較佳為20至40%) 8 30 至 90 % (較佳為45至90%) 12 NLT 50 % (較佳為NLT60%) 16 NLT 60 % (較佳為NLT 70%) 20 NLT 70 % (較佳為NLT80%) NLT :不少於（not less than) 釋出第二種活性藥物 時間(小時） 釋出％ 0.5 NLT 60% (較佳為75%) 已發現用於該劑型之噻唑啶二酮成分中賦型劑之選 擇，可顯著地影響噻唑啶二酮之釋放特性、效力與安定性。 因此，於本發明之另一具體實施例，本發明之噻唑啶二酮 成分的組成應經過挑選，俾當根據美國藥典（United States Pharmacopeia，USP) 26 版，以裝置 1，於 37°C，75 rpm， 900毫升之0.3M KCl-HCM，pH 2.0緩衝液測試時，於45分 丄jo丄υ/υ 鐘内，較佳為40分鐘内，最佳為3〇分鐘内，由該劑型釋 出之噻唑啶一酮不小於85% ,較佳為不小於9〇%及最佳為 不小於95%。 再者，該劑型之噻唑啶二鲷成分令所使用之賦型劑應經 過挑選，俾使噻唑啶二酮相關之化合物或不純物的總量在 最終之劑型内的含量不超過0 6%，較佳為不超過〇 5〇/。及最 佳為不超過0.25%且各噻唑啶二酮衍生物相關之化合物或 不純物在最終之劑型内不超過〇 25% ,較佳為不超過〇 2% 及最佳為不超過〇.1%β該噻唑啶二酮相關之化合物或不純 物在最終之劑型内的含量係由高效能液相層析（HpLC)所定 量’採用 5 微米、120A、4‘6 X 250 毫米之 YMC-ODS-AQ， 或類似管柱’移動相為〇1M乙酸銨緩衝液：乙腈：冰醋酸 (25 . 25 : 1);注射體積為4〇微升；流速為〇 7毫升/分鐘； 管柱溫度為25°C以及UV偵測器波長為269奈米。The first active drug core. Content (according to the core ° / 〇) drug 50 to 98% (preferably 75 to 95%) binding agent 0.1 to 40% (preferably 3 to 15%) absorption enhancer 0 to 20% (preferably 2 to 10%) Lubricant 0 to 5% (preferably 〇5 to 1%) Outer film: Content (% of outer film) Polymer 50 to 99% (preferably 75 Up to 95%) Flow enhancer 0 to 40% (preferably 2 to 20%) Plasticizer 0 to 25% (preferably 2 to 15%) Second active drug content (%/〇 of total dosage form) 0.1 to 20% (preferably 1 to 10%) of the drug 0.1 to 30% (preferably 1 to 15%) of the surfactant 0 to 20% (preferably 0.1 to 15%) of the pore former 0 Up to 25% (preferably 0.1 to 15%) polymer (as needed) 0 to 30% (preferably 0.1 to 20%) 1361070 When using USP Type 2 device at 37 ° C, 75 rpm, 900 ml imitation When tested in intestinal fluid (pH 7.5 phosphate buffer), the dosage form prepared according to the present invention can exhibit the following dissolution profile: release of the first active drug time (hours) release % 2 0 to 25 % (preferably 0 to 15%) 4 10 to 45 v (better 20 to 40%) 8 30 to 90% (preferably 45 to 90%) 12 NLT 50 % (preferably NLT 60%) 16 NLT 60 % (preferably NLT 70%) 20 NLT 70 % (preferably NLT80%) NLT : not less than release of the second active drug time (hours) release % 0.5 NLT 60% (preferably 75%) The thiazolidinedione component found for this formulation The choice of intermediate excipients can significantly affect the release characteristics, potency and stability of thiazolidinedione. Thus, in another embodiment of the invention, the composition of the thiazolidinedione component of the present invention should be selected according to the United States Pharmacopeia (USP) version 26, device 1, at 37 ° C, 75 rpm, 900 ml of 0.3 M KCl-HCM, pH 2.0 buffer test, within 45 minutes 丄jo丄υ / 钟 clock, preferably within 40 minutes, preferably within 3 〇 minutes, from the dosage form The thiazolidine-one is not less than 85%, preferably not less than 9% by weight and most preferably not less than 95%. Furthermore, the thiazolidine dioxime component of the dosage form should be selected such that the total amount of the compound or impurity associated with the thiazolidinedione is not more than 0% in the final dosage form. Good is no more than 〇5〇/. And preferably not more than 0.25% and the compound or impurity associated with each thiazolidinedione derivative is not more than 25%, preferably not more than 2% and most preferably not more than 0.1% in the final dosage form. The content of β-the thiazolidinedione-related compound or impurity in the final dosage form is quantified by high performance liquid chromatography (HpLC) using YMC-ODS-AQ of 5 μm, 120 A, 4′6 X 250 mm. , or similar column 'moving phase is 〇1M ammonium acetate buffer: acetonitrile: glacial acetic acid (25 . 25 : 1); injection volume is 4 〇 microliter; flow rate is 〇 7 ml / min; column temperature is 25 ° The C and UV detectors have a wavelength of 269 nm.
【實施例】 下列提供之實施例僅作為範例而非用於限制本發明之 範圍。 會施例1 採下列方式製備含有85〇毫克之二曱雙胍鹽酸鹽及15 毫克之吡格列_之控制釋放錠劑。 20 ⑧ 1361070 (佔核心組成之〇/〇) 90.54 % 4.38 % 4.58 % 第一種活性藥物 I.核心： 二曱雙胍鹽酸鹽[Examples] The following examples are provided by way of illustration only and are not intended to limit the scope of the invention. Example 1 A controlled release lozenge containing 85 mg of diterpene dihydrochloride hydrochloride and 15 mg of pioglirel was prepared in the following manner. 20 8 1361070 (占/〇 of core composition) 90.54 % 4.38 % 4.58 % First active drug I. Core: Diterpenoid hydrazine hydrochloride
聚維輞(Povidoi^K-SO1，USP 鱗酸鈉，三鹽基性(Sodium Tribasic Phosphate) 硬月旨酸鎮_ 0.5 〇/〇 1估計分子量為50,000 ;動態黏度（於2〇，10% w/v溶Polyvidone (Povidoi^K-SO1, USP sodium sulphate, Sodium Tribasic Phosphate) 估计 0.5 〇/〇1 estimated molecular weight is 50,000; dynamic viscosity (at 2〇, 10% w /v dissolve
液）=5.5-8.5 mPa . s 〇 (a) 製粒 將二甲雙胍鹽酸鹽以40網孔之篩網過篩，濾除結塊且 . 收集於乾淨的聚乙烯-内襯容器内。將聚維酮K-30與三鹽 基性碟酸鈉溶於純水中。將去除結塊之二曱雙胍鹽酸鹽加 入至上喷"流動床造粒機（top-spray fluidized bed granulator)，並於下列條件下喷灑聚維酮與三鹽基性磷酸鈉 結合溶液進行製粒：入口空氣溫度為50至70°C，霧化氣 φ 壓為1至3 bars且喷灑速率為1〇至1〇〇毫升/分鐘。 當結合溶液用完後’製成之顆粒在製粒器劑内乾燥直 到乾燥後失重小於2%。乾燥顆粒以配有相當於18網孔之 篩網的粉碎機（comil)過篩。 (b) 製錠 將硬脂酸鎂以40網孔之不鏽鋼篩網過篩且與二甲雙胍 鹽酸鹽顆粒混攪約5分鐘，混攪後以配有15/32”圓形標準 凹型打贫機（concave punches)裝置（平滑的下錠孔，上敍:孔 具有約1毫米的壓痕針）的輪壓機（r〇tary press)壓縮。 21 1361070 如上述，此孔口可藉一般製藥業使用的任何方法予以 形成。 (c) 封裝包衣（選擇性的） 核心錠劑可用Opadry材料或其他適合的水溶性的材料 封裝包覆，首先將Opadry材料，較佳為〇padryClear溶於 純水。然後於下列條件下將該〇padry溶液以包衣盤（pan water)喷灑於核心錠劑：排氣溫度為38 42充；霧化氣壓為 28至4〇psi且噴灑速率為10至15毫升/分鐘。該核心錠劑 可用封裝溶液包覆直到達成約2至4%之理論上的包覆量。 (佔外膜組成之％) 85% 5% 10% Π.外膜 纖維素醋酸酯(398-10)2 三醋酸甘油S旨(triacetin> PEG 400 乙醯基含量39.3至40.3%Liquid) = 5.5-8.5 mPa . s 〇 (a) Granulation Metformin hydrochloride was sieved through a 40 mesh screen, filtered out and agglomerated in a clean polyethylene-lined container. The povidone K-30 and the tribasic sodium silicate are dissolved in pure water. The agglomerated diterpene hydrazine hydrochloride was added to a top-spray fluidized bed granulator, and the povidone and the tribasic sodium phosphate binding solution were sprayed under the following conditions. Granulation: The inlet air temperature is 50 to 70 ° C, the atomizing gas φ pressure is 1 to 3 bars and the spraying rate is 1 Torr to 1 〇〇 ml/min. When the combined solution is used up, the finished granules are dried in the granulator until the weight loss is less than 2% after drying. The dried granules were sieved with a comil equipped with a screen equivalent to 18 mesh. (b) Ingots Magnesium stearate was sieved through a 40 mesh stainless steel screen and mixed with metformin hydrochloride pellets for about 5 minutes. After mixing, it was equipped with a 15/32" circular standard concave type depleting machine. (concave punches) device (smooth lower ingot, above: hole with about 1 mm indentation needle) compression press (r〇tary press) 21 1361070 As above, this orifice can be used in the general pharmaceutical industry Any method used is formed.(c) Package coating (optional) The core tablet can be encapsulated with Opadry material or other suitable water-soluble material. First, the Opadry material, preferably 〇padryClear, is dissolved in pure water. The 〇padry solution was then sprayed onto the core tablet as a pan water under the following conditions: an exhaust gas temperature of 38 42 charge; an atomization gas pressure of 28 to 4 psi and a spray rate of 10 to 15 ML/min. The core tablet can be coated with a potting solution until a theoretical coating of about 2 to 4% is achieved. (% of the outer membrane composition) 85% 5% 10% Π. Outer membrane cellulose acetate (398-10)2 Triacetin S (triacetin) PEG 400 Ethyl group content 39.3 to 40.3%
(a) 外膜包覆程序 將纖維素醋酸酯溶解於丙酮同時以均質器攪拌。於該 纖維素醋酸酯溶液中加入聚乙二醇pEG 4〇〇及三醋酸甘油 西曰且繼續攪拌直到溶液透明。然後採用下列條件將此透明 之外旗塗層溶液以流動床包衣機（fluidized bed __喷灑 於經封裝包覆之鍵劑：產物溫度為16至22°C ;霧化氣壓 為約3 ba且噴灑速率為120至150毫升/分鐘。將經封裝 之核心錠劑進行包覆直到得到約3%之理論上的包覆量。 ⑧ 1361070 (佔第二成份之％) 43.5 % 2.0 % 54.5 % III.第二種活性藥物層 °比格列酮鹽酸鹽 Tween 80 羥丙基甲基纖維素 將Tween 80與經丙基甲基纖維素溶解於纯水。然後將 吡格列酮鹽酸鹽分散於此溶液中。將所得之懸浮液喷灑於 上述經覆以外膜之錠劑。 實施例2 採下列方式製備含有850毫克之二甲雙胍鹽酸鹽及15 毫克之吡格列酮之控制釋放錠劑。 第一種活性藥物 I·核心： 二曱雙胍鹽酸鹽 聚維酮K-901，USP 十二烷基硫酸鈉 硬脂酸鎂 (佔核心組成之％) 88.555 % 6.368 % 4.577 % 0.5 % 23 1 估計分子量=1,000,000 ;於20°C動態黏度（10% w/v溶 液）為 300 至 700 mPa . s。 (a) 製粒 將二曱雙胍鹽酸鹽與十二烷基硫酸鈉以40網孔之篩網 過篩，濾除結塊且收集於乾淨的聚乙烯-内襯容器内。將聚 1361070 維酮K-90溶於純水中。將去除結塊之二甲雙胍鹽酸鹽與十 二烷基硫酸鈉加入至上喷流動床造粒機，並於下列條件下 喷灑聚維酮之結合溶液進行製粒：入口空氣溫度為5〇至 70C,霧化氣壓為1至3 bars且喷灑速率為1〇至1〇〇毫升 /分鐘。 當結合溶液用完後，製成之顆粒在製粒器内乾燥直到 乾燥後失重小於2%。乾燥之顆粒以配有相當於丨8網孔之 篩網的粉碎機.過篩。 (b) 製鍵 將硬脂酸鎂以40網孔之不鏽鋼篩網過篩且與二曱雙胍 - 鹽酸鹽顆粒混攪約5分鐘，混攪後以配有1 5/32”圓形標準 凹型打錠機裝置（平滑的下錠孔，上錠孔具有約i公厘的壓 痕針）的輪壓機壓縮。 如同上述’此孔口可藉一般製藥業使用的任何方法予 以形成。 • (C) 封裝包衣（選擇性的） 該核心鍵劑係以Opadry材料或其他適合的水溶性材料 進行封裝包覆，首先將Opadry材料，較佳為〇padryClear '合於純水。然後於下列條件下將此Opadry溶液以包衣盤喷 麗於核心錠劑上：排氣溫度為38至42〇c ;霧化氣壓為28 至40 psi且噴灑速率為至Η毫升/分鐘。核心錠劑係以 封裝溶液包覆直到達成約2%之理論上的包覆量。 ⑧ 1361070 II.生區 （佔外膜組成之％) 纖維素醋酸酯（398-10)4 4 85 % 三醋酸甘油酯 5% PEG 400 10% 4乙醯基含量為39.3至40.3% (a) 外膜包覆程序 將纖維素醋酸酯溶解於丙酮同時以均質器攪拌。於該 纖維素醋酸酯溶液中加入聚乙二醇400及三醋酸甘油酯以 及攪拌。然後於採用下列條件下將此包覆溶液以流動床包 衣機喷灑於經封裝包覆之錠劑上：產物溫度為16至22°C ; 霧化氣壓為3 bars且喷灑速率為120至150毫升/分鐘。將 經封裝之核心錠劑進行包覆直到得到約3%之理論上的包 覆量。 III.第二種活性藥物層 °比格列酮鹽酸鹽 Tween 80 羥丙基甲基纖維素 (佔第二種成份組成之％) 43.5 % 2.0 % 54.5 % 將Tween 80與經丙基甲基纖維素溶解於纯水。然後將 吡格列酮鹽酸鹽分散於此溶液中。然後將所得之懸浮液喷 灑於上述錠劑。 實施例3 ⑧ 1361070 採下列方式製備含有500毫克之二曱雙胍鹽酸鹽及15 毫克之吡格列酮之控制釋放錠劑。 I.第一種活性藥物 如實施例2所述之方式製備含有5 00毫克二甲雙胍之 經外膜包覆之錠劑，但其在製造錠劑時係使用化合物量杯 模具。此500毫克二甲雙胍之經外膜包覆之錠劑具有下列(a) Outer film coating procedure Cellulose acetate was dissolved in acetone while stirring with a homogenizer. To the cellulose acetate solution, polyethylene glycol pEG 4 oxime and glycerin triacetate were added and stirring was continued until the solution was transparent. The transparent outer flag coating solution was then sprayed on a fluidized bed coater under the following conditions (fluidized bed __ sprayed onto the packaged coated bond: product temperature was 16 to 22 ° C; atomization gas pressure was about 3 Ba and spray rate of 120 to 150 ml/min. The encapsulated core tablet is coated until a theoretical coating of about 3% is obtained. 8 1361070 (% of the second component) 43.5 % 2.0 % 54.5 % III. Second active drug layer 比 glitazone hydrochloride Tween 80 Hydroxypropyl methylcellulose Dissolve Tween 80 and propylmethylcellulose in pure water. Then disperse the pioglitazone hydrochloride in In the solution, the resulting suspension was sprayed onto the above-mentioned coated tablets.Example 2 A controlled release lozenge containing 850 mg of metformin hydrochloride and 15 mg of pioglitazone was prepared in the following manner. Active drug I·core: Diterpenoid hydrochloride povidone K-901, USP sodium lauryl sulfate magnesium stearate (% of core composition) 88.555 % 6.368 % 4.577 % 0.5 % 23 1 Estimated molecular weight = 1,000,000; dynamic viscosity at 20 ° C (10% w / v solution) is 3 00 to 700 mPa . s. (a) Granulation Screening of diterpene dihydrochloride hydrochloride with sodium lauryl sulfate in a 40 mesh screen, filtering out agglomerates and collecting in a clean polyethylene-liner In the container, poly 1361070 ketone K-90 was dissolved in pure water. The agglomerated metformin hydrochloride and sodium lauryl sulfate were added to an upper spray fluid bed granulator and sprayed under the following conditions. The ketone combination solution is granulated: the inlet air temperature is 5 〇 to 70 C, the atomization gas pressure is 1 to 3 bars, and the spraying rate is 1 〇 to 1 〇〇 ml/min. The granules are dried in the granulator until the weight loss is less than 2% after drying. The dried granules are sieved with a pulverizer equipped with a sieve equivalent to 丨8 mesh. (b) The key is made of magnesium stearate to 40 The mesh stainless steel screen is sieved and mixed with the diterpene-hydrochloride salt particles for about 5 minutes. After mixing, it is equipped with a 15/32" circular standard concave ingot machine (smooth lower spindle hole, The upper press has a wheel press compression of about i mm of indentation needle. As mentioned above, this orifice can be used by any method used in the general pharmaceutical industry. (C) Encapsulation coating (optional) The core bond is encapsulated with Opadry material or other suitable water-soluble material. The Opadry material, preferably 〇padryClear', is first combined with pure water. The Opadry solution was then sprayed onto the core tablet with a coating pan under the following conditions: an exhaust temperature of 38 to 42 〇c; an atomization pressure of 28 to 40 psi and a spraying rate of Ηml/min. The core tablet is coated with a potting solution until a theoretical coating of about 2% is achieved. 8 1361070 II. Raw area (% of outer membrane composition) Cellulose acetate (398-10) 4 4 85 % Triacetin 5% PEG 400 10% 4 Ethyl group content is 39.3 to 40.3% (a) The outer film coating procedure dissolves the cellulose acetate in acetone while stirring with a homogenizer. Polyethylene glycol 400 and triacetin were added to the cellulose acetate solution and stirred. The coating solution was then sprayed onto the packaged coated tablets using a fluid bed coater under the following conditions: product temperature 16 to 22 ° C; atomization gas pressure 3 bars and spray rate 120 Up to 150 ml / min. The encapsulated core tablet was coated until a theoretical coating of about 3% was obtained. III. Second active drug layer °Tigrenide hydrochloride Tween 80 Hydroxypropyl methylcellulose (% of the second component) 43.5 % 2.0 % 54.5 % Tween 80 and propylmethyl Cellulose is dissolved in pure water. Pioglitazone hydrochloride is then dispersed in this solution. The resulting suspension is then sprayed onto the above tablet. Example 3 8 1361070 A controlled release lozenge containing 500 mg of dioxonium hydrochloride and 15 mg of pioglitazone was prepared in the following manner. I. First active drug An outer film coated tablet containing 500 mg of metformin was prepared in the manner described in Example 2, but in the manufacture of the tablet, a compound measuring cup mold was used. The 500 mg metformin-coated outer coating has the following
成分： 核心 二曱雙胍鹽酸鹽 500毫克/鍵 聚維酮K-90，USP 35.96毫克/錠 十二烷基硫酸鈉，NF 25.84毫克/錠 硬脂酸鎂，NF 2.82毫克/銳 封裝包衣 Opadry Clear (YS-1-7006) 23.53毫克/錠 外膜包衣 纖維素醋酸酯，398-10，NF 23.56毫克/錠 三醋酸甘油酯，USP 1.39毫克/鍵 聚乙二醇400，NF 2.77毫克/錠 總重 615.87毫克/鍵 II.第二種活性藥物層 將立即釋放量之吡格列酮鹽酸鹽施用於步驟I製備之 含5 00毫克二曱雙胍鹽酸鹽之經外膜包覆之錠劑。最終之 錠劑具有下列成分： 26 ⑧ 1361070 含二甲雙胍鹽酸鹽之經外膜包覆之錠劑 615.87毫克/疑 。比格列酮包衣 。比格列酮鹽酸鹽 16.53毫克/錠 Tween 80 2.0毫克/鍵 Polyplasdone XL 15.0毫克/疑 Opadry Clear (YS-1-7006) 8.47毫克/鍵 彩色包衣 Opadry White 10.0毫克/鍵 光滑包衣 堪地里拉(Candelilla)蠟粉 2.0毫克/旋Ingredients: Core Diterpenoid Hydrochloride 500 mg / Bond Povidone K-90, USP 35.96 mg / tablet sodium lauryl sulfate, NF 25.84 mg / tablet magnesium stearate, NF 2.82 mg / sharp package Opadry Clear (YS-1-7006) 23.53 mg / ingot coated cellulose acetate, 398-10, NF 23.56 mg / ingot triacetin, USP 1.39 mg / bond polyethylene glycol 400, NF 2.77 mg / Ingot total weight 615.87 mg / bond II. Second active drug layer The immediate release amount of pioglitazone hydrochloride was applied to the outer film coated lozenge containing 500 mg of diterpene biguanide hydrochloride prepared in step I. . The final lozenge has the following composition: 26 8 1361070 Over-film coated lozenge containing metformin hydrochloride 615.87 mg/suspect. Biglitazone coating. Biglitazone hydrochloride 16.53 mg / tablet Tween 80 2.0 mg / bond Polyplasdone XL 15.0 mg / suspect Opadry Clear (YS-1-7006) 8.47 mg / key color coating Opadry White 10.0 mg / key smooth coating Candelilla wax powder 2.0 mg / whirl
吡格列酮包衣係直接施用於500毫克二曱雙胍鹽酸鹽 之經外膜包覆之錠劑上。吡格列酮包衣係藉由使用均質器 將0.252公斤之Opadry Clear、0.269公斤之交聯聚維酮 (Polyplasdone) XL 以及 0_036 公斤之 Tween 80 溶解於 9.908 公斤之純水中製備而成。一旦這些原料都溶解了，將0.296 公斤之吡格列酮鹽酸鹽分散至此溶液並均質化。經均質化 之分散液繼而以24” O’Hara Labcoat III包衣盤於下列條件 下施用至500毫克二甲雙胍鹽酸鹽之經外膜包覆之錠劑 喷灑速率 排氣溫度 霧化氣壓 包衣盤之速度 入口氣流The pioglitazone coating was applied directly to an outer film coated lozenge of 500 mg of diterpene biguanide hydrochloride. The pioglitazone coating was prepared by dissolving 0.252 kg of Opadry Clear, 0.269 kg of PEG (Polyplasdone) XL and 0_036 kg of Tween 80 in 9.908 kg of pure water using a homogenizer. Once these materials were dissolved, 0.296 kg of pioglitazone hydrochloride was dispersed into the solution and homogenized. The homogenized dispersion was then applied to a 500" O'Hara Labcoat III coating pan to 500 mg of metformin hydrochloride via an outer membrane coated lozenge spray rate exhaust temperature atomized air pressure coating under the following conditions. Disk speed inlet airflow
15至27毫升/分鐘 42 至 47°C 25 psi 5 至 9 rpm 300 至 400 CFM ⑧ 1361070 一旦將吡格列酮包衣施用至500毫克二甲雙胍鹽酸鹽 之經外膜包覆之錠劑上，可將Opadry White美觀的或彩色 包衣施用至該經吡格列酮包覆之錠劑上。彩色包衣係藉由 將0.179公斤之Opadry White分散於1.791公斤之纯水中 而製備。此Opadry White懸浮液繼而以24”0’Hara Labcoat III包衣盤於下列條件下施用至該經吡格列酮包覆之錠劑：15 to 27 ml/min 42 to 47 ° C 25 psi 5 to 9 rpm 300 to 400 CFM 8 1361070 Once the pioglitazone coating is applied to 500 mg of metformin hydrochloride on the outer film coated lozenge, Opadry An aesthetically pleasing or colored coating is applied to the pioglitazone coated lozenge. The color coating was prepared by dispersing 0.179 kg of Opadry White in 1.791 kg of pure water. This Opadry White suspension was then applied to the pioglitazone-coated lozenge using a 24"0'Hara Labcoat III coating pan under the following conditions:
喷灑速率 20至35毫升/分鐘 排氣溫度 35 至 45°C 霧化氣壓 25 psi 包衣盤之速度 9 rpm 入口氣流 390 至 500 CFMSpray rate 20 to 35 ml/min Exhaust temperature 35 to 45 °C Atomization pressure 25 psi Coating speed 9 rpm Inlet airflow 390 to 500 CFM
當施用彩色包衣後，將該錠劑以0.036公斤之堪地里 拉壞粉磨光。 實施例Λ_ 採下列方式製備含有500毫克之二曱雙胍鹽酸鹽及15 毫克之。比格列酮之控制釋放錠劑。 l- 種活性藥物 如實施例2所述之方式製備含有5〇〇毫克二曱雙胍之 經外膜包覆之錠劑’但其在製造錠劑時係使用化合物量杯 模具°此500毫克二甲雙胍之經外膜包覆之錠劑具有下列 成分： ⑧ 1361070 核心 二甲雙胍鹽酸鹽 500毫克/錠 聚維酮K-90，USP 35.96毫克/錠 十二烷基硫酸鈉，NF 25.84毫克/錠 硬脂酸鎂，NF 2.82毫克/錠 封裝包衣 Opadry Clear (YS-1-7006) 23.53毫克/錠 外膜包衣 纖維素醋酸酯，398-10，NF 23.56毫克/錠 三醋酸甘油酯，USP 1.39毫克/錠 聚乙二醇400，NF 2.77毫克/錠 總重 615.87毫克/錠 II.第二種活性藥物層 將立即釋放量之吡格列酮鹽酸鹽施用於步驟i製備之 含5 00毫克二曱雙胍鹽酸鹽之經封裝包覆之錠劑。最終之 錠劑具有下列成分： 615.87毫克/錠 13.8毫克/錠 16.53毫克/錠 2.0毫克/錠 4.27毫克/鍵 8.47毫克/錠 8.10毫克/錠 0.2毫克/録： 含二甲雙胍鹽酸鹽之經外膜包覆之錠劑 •封裝包衣After application of the color coat, the tablet was polished with 0.036 kg of inferior mala powder. EXAMPLES 制备 Preparation of 500 mg of dioxonium hydrochloride and 15 mg were prepared in the following manner. Controlled release lozenges of geglitazone. L- Active Drugs An outer film-coated tablet containing 5 mg of diterpene bismuth was prepared as described in Example 2, but in the manufacture of tablets, a compound measuring cup mold was used. This 500 mg metformin was used. The outer film coated tablet has the following composition: 8 1361070 Core metformin hydrochloride 500 mg / tablet povidone K-90, USP 35.96 mg / tablet sodium lauryl sulfate, NF 25.84 mg / tablet stearic acid Magnesium, NF 2.82 mg/ingle encapsulated coating Opadry Clear (YS-1-7006) 23.53 mg/ingot outer coating cellulose acetate, 398-10, NF 23.56 mg/indicole triacetin, USP 1.39 mg/ Ingot polyethylene glycol 400, NF 2.77 mg / ingot total weight 615.87 mg / ingot II. Second active drug layer The immediate release amount of pioglitazone hydrochloride was applied to the 500 mg of diterpene guanidine hydrochloride prepared in step i A package of salt coated with a salt. The final lozenge has the following ingredients: 615.87 mg / ingot 13.8 mg / ingot 16.53 mg / ingot 2.0 mg / ingot 4.27 mg / key 8.47 mg / ingot 8.10 mg / ingot 0.2 mg / recorded: the outer membrane containing metformin hydrochloride Coated lozenge • encapsulation coating
Opadry Clear (YS-1-7006) 吡格列酮包衣 °比格列酮鹽酸鹽 Tween 80 氯化鈉Opadry Clear (YS-1-7006) pioglitazone coating ° glitazone hydrochloride Tween 80 sodium chloride
Opadry Clear (YS-1-7006) 彩色包衣 Opadry White 光滑包衣 堪地里拉蠟粉 29 ⑧ 1361070 封裝包衣溶液係藉由將0.258公斤之Opadry Clear溶 解於2.576公斤之純水中而製備以及使用 24” O’Hara Labcoat III包衣盤將該溶液喷灑於約12.088公斤之500毫 克二甲雙胍鹽酸鹽經外膜包覆之錠劑上。該封裝包衣係於 下列條件下施用 喷灑速率 排氣溫度 霧化氣壓 包衣盤之速度 入口氣流 20至35毫升/分鐘 35 至 45。。 25 psi 9 rpmOpadry Clear (YS-1-7006) Color Coating Opadry White Smooth Coating Cantilra Wax Powder 29 8 1361070 Package coating solution is prepared and used by dissolving 0.258 kg of Opadry Clear in 2.576 kg of pure water. 24" O'Hara Labcoat III coating tray This solution was sprayed onto an outer film coated lozenge of about 12.088 kg of 500 mg of metformin hydrochloride. The package coating was applied under the following conditions. Gas temperature atomizing air pressure coating tray speed inlet air flow 20 to 35 ml / min 35 to 45. 25 psi 9 rpm
390 至 500 CFM - 吡格列酮包衣係施用於500毫克二曱雙胍鹽酸鹽之經 外膜包覆之錠劑上。吡格列酮包衣係藉由使用均質器將 0.040公斤之Opadry Clear、0.085公斤之氣化納以及0.040 公斤之Tween 80溶解於4.915公斤之純水中製備而成。一 旦這些原料都溶解了，將0.328公斤之吡格列酮鹽酸鹽分 • 散至此溶液並均質化。經均質化之分散液繼而以 24” O’Hara Labcoat III包衣盤於下列條件下施用至500毫克二 曱雙胍鹽酸鹽之經外膜包覆之錠劑上： 喷灑速率 排氣溫度 霧化氣壓 典型氣壓(Pattern Air Pressure) 包衣盤之速度 入口氣流 10至30毫升/喷射器/分鐘390 to 500 CFM - Pioglitazone coating was applied to an outer film coated lozenge of 500 mg of diterpene biguanide hydrochloride. The pioglitazone coating was prepared by dissolving 0.040 kg of Opadry Clear, 0.085 kg of gasified sodium, and 0.040 kg of Tween 80 in 4.915 kg of purified water using a homogenizer. Once these materials were dissolved, 0.328 kg of pioglitazone hydrochloride was dispensed into the solution and homogenized. The homogenized dispersion was then applied to a 500" O'Hara Labcoat III coated pan to the outer film coated lozenge of 500 mg of diterpene hydrazine hydrochloride under the following conditions: Spray rate exhaust temperature fog Pattern Air Pressure (Pattern Air Pressure) The speed of the coating tray. Inlet airflow 10 to 30 ml / ejector / minute
35 至 45°C 20 至 40 psi 20 至 40 psi 8 至 12 rpm35 to 45 ° C 20 to 40 psi 20 to 40 psi 8 to 12 rpm
250 至 450 CFM 30 1361070 一旦將吡格列酮包衣施用至5 00毫克二甲雙胍鹽酸鹽 之經外膜包覆之錠劑上，可將Opadry White美觀的或彩色 包衣施用至該經吡格列酮包覆之錠劑上。彩色包衣係藉由 將0.159公斤之Opadry White分散於1.5 85公斤之纯水中 而製備。此Opadry White懸浮液繼而以類似上述施用封裝 包衣之條件施用至該經吡格列酮包覆之錠劑。當施用彩色 包衣後，將該錠劑以0.004公斤之堪地里拉蠟粉磨光。 實施例5 採下列方式製備含有1000毫克之二甲雙胍鹽酸鹽及 30毫克之吡格列酮之控制釋放錠劑。 I.第一種活性藥物 如實施例3所述之方式製備含有1000毫克二曱雙胍之 經外膜包覆之錠劑。該1〇〇〇毫克二甲雙胍之經外膜包覆之 錠劑具有下列成分：250 to 450 CFM 30 1361070 Once the pioglitazone coating is applied to the outer film coated tablet of 500 mg of metformin hydrochloride, an Opadry White aesthetic or color coating can be applied to the pioglitazone coated ingot. On the agent. The color coating was prepared by dispersing 0.159 kg of Opadry White in 1.5 85 kg of pure water. This Opadry White suspension is then applied to the pioglitazone-coated lozenge under conditions similar to those described above for application of the encapsulating coating. After application of the color coat, the tablet was polished with 0.004 kg of candelabra wax. Example 5 A controlled release lozenge containing 1000 mg of metformin hydrochloride and 30 mg of pioglitazone was prepared in the following manner. I. First Active Drug An outer film coated lozenge containing 1000 mg of diterpene biguanide was prepared as described in Example 3. The 1 mg mg metformin-coated outer coating has the following composition:
核心 二曱雙胍鹽酸鹽 1000毫克/錠 聚維酮K-90，USP 78.0毫克/錠 十二烷基疏酸鈉，NF 51.69毫克/錠 硬脂酸鎂，NF 5.66毫克/錠 封裝包衣 Opadry Clear (YS-1-7006) 47.05毫克/錠 外膜包衣 纖維素醋酸酯，398-10，NF 15.77毫克/旋 三醋酸甘油酯，USP 0.92毫克/錠 聚乙二醇400，NF 1.85毫克/錠 總重 1201.0毫克/錠 ⑧ 1361070 II.第二種活性藥物 將立即釋故量之吡格列酮鹽酸鹽施用於步驟I製備之 含1000毫克二甲雙胍鹽酸鹽之經外膜包覆之錠劑。最終之 錠劑具有下列成分： 含二甲雙胍鹽酸鹽之經外膜包覆之錠劑 1201.0毫克/錠 封裝包衣 16.0毫克/疑 33.06毫克/錠 4.27毫克/敍： 3.0毫克/鍵 20.27毫克/錠 0.40毫克/疑Core diterpenoid hydrochloride 1000 mg/povidone povidone K-90, USP 78.0 mg/indium lauryl sodium sulphate, NF 51.69 mg/paste magnesium stearate, NF 5.66 mg/indium package coating Opadry Clear (YS-1-7006) 47.05 mg / ingot coated cellulose acetate, 398-10, NF 15.77 mg / triacetin, USP 0.92 mg / tablet polyethylene glycol 400, NF 1.85 mg / Ingot total weight 1201.0 mg / ingot 8 1361070 II. Second active drug Immediately release the amount of pioglitazone hydrochloride to the outer film coated lozenge containing 1000 mg of metformin hydrochloride prepared in step I. The final lozenge has the following ingredients: Outer film coated lozenge containing metformin hydrochloride 1201.0 mg/inglon encapsulating coating 16.0 mg/suspect 33.06 mg/ingot 4.27 mg/shr: 3.0 mg/bond 20.27 mg/ingot 0.40 mg / doubt
Opadry Clear (YS-1-7006) 吡格列酮包衣 °比格列酮鹽酸鹽 氣化納Opadry Clear (YS-1-7006) pioglitazone coating ° glitazone hydrochloride gasification
Opadry Clear (YS-1-7006) 彩色包衣Opadry Clear (YS-1-7006) color coat
Opadry II White (Y-22-7719) 光滑包衣 堪地里拉蠟粉 封裝包衣係藉由將〇. 174公斤之Opadry Clear分散於 3.478公斤之乙醇中且混合該分散液1 5分鐘而製備。然後 使用 24” O’Hara Labcoat III包衣盤將該分散液喷灑於約 13.174公斤之1000毫克二曱雙胍鹽酸鹽經外膜包覆之錠劑 上。該封裝包衣係於下列條件下施用至該1000毫克二曱雙 胍鹽酸鹽經外膜包覆之錠劑： 32 ⑧ 1361070Opadry II White (Y-22-7719) Smooth Coating The Candid Wax Powder package was prepared by dispersing 174 kg of Opadry Clear in 3.478 kg of ethanol and mixing the dispersion for 15 minutes. The dispersion was then sprayed onto an outer film coated lozenge of about 13.174 kg of 1000 mg of diterpene biguanide using a 24" O'Hara Labcoat III coating pan. The package was under the following conditions. Applying to the 1000 mg of diterpene biguanide hydrochloride coated with an outer membrane: 32 8 1361070
喷灑速率 10至30毫升/喷射器/分鐘 排氣溫度 25 至 45°C 霧化氣壓 20 至 40 psi 包衣盤之速度 6 至 12 rpm 典型氣壓 20 至 40 psi 入口氣流 250 至 450 CFM 然後將吡格列酮包衣施用至1 〇〇〇毫克二曱雙胍鹽酸鹽 之經外膜包覆之錠劑上。吡格列酮包衣係藉由使用均質器 將0.036公斤之Op adry Clear及0.046公斤之氣化納溶解於 5.344公斤之乙醇中製備而成。一旦這些原料都溶解了，將 0.359公斤K I歹_鹽酸鹽分^:至此ί容液並均質化。經均 質化之分散液繼而以24” O’Hara Labcoat III包衣盤於下列 條件下施用至經封裝包覆之1000毫克二曱雙胍鹽酸鹽之 經外膜包覆之錠劑上： 喷灑速率 排氣溫度 霧化氣壓 包衣盤之速度 典型氣壓 入口氣流 10至30毫升/喷射器/分鐘Spray rate 10 to 30 ml / ejector / minute exhaust temperature 25 to 45 ° C atomizing air pressure 20 to 40 psi coating plate speed 6 to 12 rpm typical air pressure 20 to 40 psi inlet air flow 250 to 450 CFM then The pioglitazone coating was applied to an outer film coated lozenge of 1 mg of diterpene diterpene hydrochloride. The pioglitazone coating was prepared by dissolving 0.036 kg of Op adry Clear and 0.046 kg of gasified sodium in 5.344 kg of ethanol using a homogenizer. Once these materials have dissolved, 0.359 kg of K I 歹 _ hydrochloride is divided into: to this 395 solution and homogenized. The homogenized dispersion was then applied to a 24" O'Hara Labcoat III coating pan onto an outer film coated lozenge of 1000 mg of diterpene dihydrochloride hydrochloride encapsulated under the following conditions: Rate exhaust temperature atomizing air pressure coating tray speed typical air pressure inlet airflow 10 to 30 ml / ejector / minute
25 至 45°C 20 至 40 psi 6 至.12 rpm 20 至 40 psi25 to 45°C 20 to 40 psi 6 to .12 rpm 20 to 40 psi
250 至 450 CFM 一旦施用該°比+格列_包衣，可將Opadry White美觀的 或彩色包衣施用至該經吡格列酮包覆之錠劑上。彩色包衣 ⑧ 1361070 係藉由將0.220公斤之Opadry II White分散於4.407公斤 之乙醇中而製備。此Opadry II White懸浮液繼而以類似上 述封裝包衣之條件使用24” O’Hara Labcoat III包衣盤施用 至該經吡格列酮包覆之錠劑上。當施用彩色包衣後，將該 錠劑以0.004公斤之堪地里拉蠟粉磨光。 實施例6 採下列方式製備含有1000毫克之二甲雙胍鹽酸鹽及 3 0毫克之吡格列酮之控制釋放錠劑。 I.第一種活性藥物 如實施例3所述之方式製備含有1000毫克二曱雙胍之 經外膜包覆之錠劑。該1000毫克二曱雙胍之經外膜包覆之 錠劑具有下列成分： 二曱雙胍鹽酸鹽 聚維酮K-90，USP 十二烷基硫酸鈉，NF 硬脂酸鎂，NF 封裝包衣 Opadry Clear (YS-1-7006) 外膜包衣 纖維素醋酸酯，398-10，NF 三醋酸甘油酯，USP 聚乙二醇400，NF 總重 1000毫克/錠 78.0毫克/錠 51.69毫克/敍： 5.65毫克/錠 47.05毫克/錠 15.77毫克/敍： 0.92毫克/錠 1.85毫克/錠 1201.0毫克/錠 ⑧ 1361070 II.第二種活性藥物 將立即釋故量之吡格列酮鹽酸鹽施用於步驟I製備之 含1000毫克二甲雙脈.鹽酸鹽之經外膜包覆之錠劑。最終之 錠劑具有下列成分： 含二曱雙胍鹽酸鹽之經外膜包覆之錠劑 封裝包衣 Opadry Clear (YS-1-7006) 吡格列酮包衣 °比格列酮鹽酸鹽 氣化納 Opadry Clear (YS-1-7006) 彩色包衣 Opadry II White (Y-22-7719) 光滑包衣 堪地里拉蠟粉 1201.0毫克/錠 21.0毫克/錢 33.06毫克/錠 5.0毫克/錠 3.7毫克/鍵 21.54毫克/錠 0.40毫克/鍵 封裝包衣係施用於該1000毫克二甲雙胍鹽酸鹽經外 膜包覆之錠劑。封裝包衣係藉由將0.229公斤之Opadry Clear分散於4.5 73公斤之酒精USP且分散15分鐘製備而 成。然後於下列條件使用24”0’Hara Labcoat III包衣盤以 噴嘴尖頭設定於4±2”由固定床上方（top of the static bed)喷 灑此分散液至約13.08公斤之1000毫克二甲雙胍鹽酸鹽錠 35 ⑧ 1361070 劑核心上： 喷灑速率 25±10毫升/噴射器/分鐘 排氣溫度 25〇C+5〇C 霧化氣壓 10 至 40 psi 包衣盤之速度 4 至 9 rpm 供應氣流 200+100 CFM 典型氣壓 10 至 40 psi 於包覆程序中持續攪拌該封裝包衣分散液直到使用完 畢0 然後將。比格列酮包衣施用至該經封裝包覆之1 〇〇〇毫 克二甲雙胍鹽酸鹽之經外膜包覆之錠劑。該吡格列酮包衣 係藉由混合4_434公斤之酒精USP與1.250公斤之纯水（乙 醇與纯水之比例約為78:22)，再緩慢將〇 〇4〇公斤之Opadry Clear分散至該溶劑混合物中製備而成。當分散〇padry Clear時，進行均質化處理約1〇分鐘。當均質化該〇padry Clear分散液時’於該分散液中加入〇 〇54公斤之氣化鈉， 且將其均質化约2分鐘。氣化鈉均質化後，緩慢地將〇 36〇 公斤之》比格列酮鹽酸鹽分散至該溶劑混合物，然後進行均 質化約10分鐘。當吡格列酮鹽酸鹽均質化後，由混合容器 中取出均質器，改置入空氣擾拌器（air mixer)，繼續再擾拌 1 5分鐘。包覆程序中持續攪拌該吡格列酮懸浮液直到該懸 浮液使用完畢。於下列條件下使用24” 〇，Hara Labcoat hi 包衣盤以喷嘴尖頭設定於4±2”由固定床上方將該。比格列酮 36 1361070 鹽酸鹽懸浮液施用至1000毫克二甲雙胍鹽酸鹽之經外膜 包覆之錠劑核心： 喷灑速率 排氣溫度 霧化氣壓 包衣盤之速度 典型氣壓 供應氣流250 to 450 CFM Once the ° ratio + grid coat is applied, an Opadry White aesthetic or color coat can be applied to the pioglitazone coated lozenge. Color coating 8 1361070 was prepared by dispersing 0.220 kg of Opadry II White in 4.407 kg of ethanol. This Opadry II White suspension was then applied to the pioglitazone-coated lozenge using a 24" O'Hara Labcoat III coating pan under conditions similar to the above-described encapsulating coating. When a color coating was applied, the tablet was 0.004 kg of Candida wax powder was polished. Example 6 A controlled release lozenge containing 1000 mg of metformin hydrochloride and 30 mg of pioglitazone was prepared in the following manner: I. The first active drug was as in Example 3. An outer film coated lozenge containing 1000 mg of diterpene bismuth is prepared in the manner described above. The 1000 mg diterpene bismuth outer coating coated tablet has the following composition: Diterpenoid bismuth hydrochloride povidone K- 90, USP sodium lauryl sulfate, NF magnesium stearate, NF package coating Opadry Clear (YS-1-7006) outer film coated cellulose acetate, 398-10, NF triacetin, USP poly Ethylene glycol 400, NF total weight 1000 mg / spindle 78.0 mg / spindle 51.69 mg / Syria: 5.65 mg / tablet 47.05 mg / ingot 15.77 mg / Syria: 0.92 mg / ingot 1.85 mg / ingot 1201.0 mg / ingot 8 1361070 II. The second active drug will immediately release the amount of pyridin The hydrochloride salt is applied to the outer membrane coated lozenge containing 1000 mg of dimethyl succinate hydrochloride prepared in step I. The final lozenge has the following composition: the outer membrane pack containing diterpene biguanide hydrochloride Overlay package coating Opadry Clear (YS-1-7006) pioglitazone coating ° glitazone hydrochloride gasification nano Opadry Clear (YS-1-7006) color coating Opadry II White (Y-22- 7719) Smooth coating Candiola wax powder 1201.0 mg / ingot 21.0 mg / kg 33.06 mg / ingot 5.0 mg / ingot 3.7 mg / bond 21.54 mg / ingot 0.40 mg / bond encapsulation coating applied to the 1000 mg metformin hydrochloride The salt is coated with the outer film. The package is prepared by dispersing 0.229 kg of Opadry Clear in 4.5 73 kg of alcohol USP and dispersing for 15 minutes. Then use 24"0'Hara Labcoat III under the following conditions. The coating pan was sprayed with a nozzle tip at 4 ± 2" from the top of the static bed to about 13.08 kg of 1000 mg of metformin hydrochloride ingot 35 8 1361070 core: spray Rate 25 ± 10 ml / ejector / minute exhaust temperature 25 〇 C + 5 〇 C Atomizing pressure 10 to 40 psi Coating speed 4 to 9 rpm Supply airflow 200+100 CFM Typical air pressure 10 to 40 psi Continue to stir the package dispersion in the coating procedure until 0 is used. The gliglitazone coating is applied to the encapsulated coated 1 〇〇〇 milligram of metformin hydrochloride vial coated lozenge. The pioglitazone coating is prepared by mixing 4_434 kg of alcohol USP with 1.250 kg of pure water (the ratio of ethanol to pure water is about 78:22), and slowly dispersing 4 kg of Opadry Clear into the solvent mixture. Prepared. When the 〇padry Clear is dispersed, homogenization is carried out for about 1 minute. When the 〇padry Clear dispersion was homogenized, 54 kg of sodium hydride was added to the dispersion, and it was homogenized for about 2 minutes. After homogenization of the vaporized sodium, 〇36〇 kg of glitazone ketone hydrochloride was slowly dispersed to the solvent mixture, followed by homogenization for about 10 minutes. When the pioglitazone hydrochloride was homogenized, the homogenizer was removed from the mixing vessel and replaced with an air mixer and the mixture was further agitated for 15 minutes. The pioglitazone suspension is continuously stirred in the coating procedure until the suspension is used. The 24" 使用 was used under the following conditions, and the Hara Labcoat hi coating pan was set at 4 ± 2" with the nozzle tip on the fixed bed. Biglitazone 36 1361070 Hydrochloride suspension applied to 1000 mg of metformin hydrochloride via the outer membrane coated lozenge core: Spray rate Exhaust temperature Atomization pressure Coating tray speed Typical air pressure Supply airflow
25±10毫升/喷射器/分鐘 25〇C±5〇C 10 至 40 psi 4 至 9 rpm 10 至 40 psi 200±100 CFM 當該吡格列酮包衣施用至經封裝包覆之1000毫克二 甲雙胍鹽酸鹽之經外膜包覆之錠劑後，可將Opadry II White美觀的包衣施用至該經吡格列酮包覆之錠劑上。該美 觀的包衣係藉由將 0.235 公斤之 Opadry II White (YS-22-7719)分散於4.691公斤之酒精USP且混合該分散 液約一小時後製備而成。然後於下列條件下使用 24” O’Hara Labcoat III包衣盤以喷嘴尖頭設定於4±2”由固定床 上方將該Opadry II White分散液喷灑至該經吡格列酮鹽酸 鹽包覆之錠劑 25±10毫升/喷射器/分鐘 25〇C±5〇C 10 至 40 psi 4 至 9 rpm 200+100 CFM 10 至 40 psi 喷灑速率 排氣溫度 霧化氣壓 包衣盤之速度 供應氣流 典型氣壓 ⑧ 1361070 於包覆程序中持續攪拌該彩色包衣分散液直到該分散 液使用完畢。 當使用完該美觀之包衣懸浮液後，將該錠劑以包衣盤 轉速約2至8 rpm與排氣溫度為25〇c±5<t的條件下於包衣 盤中進行乾燥約5分鐘》當錠劑乾燥後，關閉排氣口並調 整包衣盤之轉速至3至4 rpm，以及將經過6〇網孔篩網過 篩之0.004公斤的堪地里拉蠟粉喷灑至該錠劑。當錠劑在 蠟粉中轉動約5分鐘之後打開排氣口再繼續轉動1〇分鐘。 磨光完成後之錠劑以USP裝置！型於1〇〇rpm、pH2 〇 HC1-0.3MKC1緩衝液中進行測試時，可顯示出下列吡格列 酮鹽酸鹽之溶離基本資料： 時間 吡格列酮釋出％ 10分鐘 42% 20分鐘 79% 30分鐘 95% 45分鐘 102 %25 ± 10 ml / ejector / minute 25 〇 C ± 5 〇 C 10 to 40 psi 4 to 9 rpm 10 to 40 psi 200 ± 100 CFM When the pioglitazone coating is applied to the encapsulated 1000 mg of metformin hydrochloride After the outer film coated lozenge, an aesthetically pleasing coating of Opadry II White can be applied to the pioglitazone coated lozenge. The cosmetic coating was prepared by dispersing 0.235 kg of Opadry II White (YS-22-7719) in 4.691 kg of alcohol USP and mixing the dispersion for about one hour. The Opadry II White dispersion was then sprayed onto the pioglitazone hydrochloride coated ingot by a 24" O'Hara Labcoat III coating pan with a nozzle tip set at 4 ± 2" under the following conditions. 25±10ml/injector/minute 25〇C±5〇C 10 to 40 psi 4 to 9 rpm 200+100 CFM 10 to 40 psi Spray rate exhaust temperature atomizing air pressure coating speed supply air supply typical Air pressure 8 1361070 The color coating dispersion was continuously stirred in the coating procedure until the dispersion was used. After the aesthetic coating suspension is used, the tablet is dried in a coating pan at a coating tray speed of about 2 to 8 rpm and an exhaust temperature of 25 〇 c ± 5 ° t. Minutes: When the tablet is dry, close the vent and adjust the speed of the coating pan to 3 to 4 rpm, and spray 0.004 kg of kanilla wax powder through the 6-inch mesh screen to the ingot. Agent. When the tablet was rotated in the wax for about 5 minutes, the vent was opened and the rotation continued for 1 minute. After the polishing is completed, the tablet is USP device! When tested in 1 rpm, pH 2 〇HC1-0.3MKC1 buffer, the following basic information on the dissolution of pioglitazone hydrochloride can be shown: Time pioglitazone release % 10 minutes 42% 20 minutes 79% 30 minutes 95% 45 minutes, 102%
.使用5微米、120A、4.6 X 250毫米之 YM ODS 移動相為〇lM乙酸按緩衝液：乙猜： 冰醋酸（25 : 25 . 1、 .〇 ,注射體積為40微升；流速為〇 7毫升 /分鐘；管枝温。 度為25 C且UV偵測器波長為269争米之 IIPIX進行测詁 不、术 時’磨光後的鍵劑亦含有下列η比格列酮相關 ⑧ 1361070 化合物。 名稱 相對滯留時間 ----- ------------ 含量 RS-1 0.7 N.D.* 0比格列酮 1.0 RS-2 1.5 0.03 RS-3 3.4 0.04 RS-4 1.2 0.03 RS-5 2.8 0.04 *N.D.=未測得Use a 5 μm, 120 A, 4.6 X 250 mm YM ODS mobile phase as 〇lM acetic acid in buffer: B guess: glacial acetic acid (25: 25.1, .〇, injection volume 40 μl; flow rate 〇7 ML/min; tube temperature. The temperature is 25 C and the UV detector wavelength is 269. IIPIX does not measure the time. The polished 'keys also contain the following η glitazone related 8 1361070 compound Name relative residence time ----------------- Content RS-1 0.7 ND* 0 glitazone 1.0 RS-2 1.5 0.03 RS-3 3.4 0.04 RS-4 1.2 0.03 RS-5 2.8 0.04 *ND=not measured
RS -1為（+/-)-5-[p-[2-(5-乙基-2-n比咬基）乙氧基]苯甲 基]-5-羥基-2,4-噻唑啶二酮。 RS-2為（ζ)-5-[Ρ-[2-(5·乙基-2-。比啶基）乙氧基]苯亞甲 基]-2,4-噻唑啶二酮。 RS-3為（+/-)-5-[ρ-[2-(5-乙基-2-»比啶基）乙氧基]苯曱 基]-3-[2-(5-乙基-2-吡啶基）乙基]_2,4-噻唑啶二酮。 RS-4 為（+/-)-乙基·2-氨基甲醯基硫 (carbamoyltio)-3-[4-[2-(5 -乙基- 2-° 比咬基）乙氧基]苯基 _]丙 酸酯。 RS-5為乙基-3-p-[2-(5-乙基-2-吡啶基）乙氧基]苯基·丙 酸酯* 將最後經磨光的鍵劑包裝於100 cc之HDPE瓶，其含 有 2 克之 SORB-IT®乾燥小筒（desiccant canister)且於 40 1361070 °C，75°/。相對濕度之加速安定條件 芮仔二個月。儲存後， 將該最後經磨光的錠劑以USP裝置]荆， 1 型（type 1)於 100 rpm、PH 2.〇、HC1-0.3M KC1 緩衝液中逸仁 w T進仃測試，可顯示出 下列°比格列酮鹽酸之溶離基本資料： 麵 吡格列飼釋*〇人 10分鐘 38% 20分鐘 73% 30分鐘 92% 45分鐘 101 % 當藉由使用 5 微米、120A、4 YMC-ODS-AQ管柱；移動相為RS-1 is (+/-)-5-[p-[2-(5-ethyl-2-n ratio) ethoxy]benzyl]-5-hydroxy-2,4-thiazolidine Dione. RS-2 is (ζ)-5-[Ρ-[2-(5·ethyl-2-pyridinyl)ethoxy]phenylmethylene]-2,4-thiazolidinone. RS-3 is (+/-)-5-[ρ-[2-(5-ethyl-2-»pyridyl)ethoxy]phenyl)]-3-[2-(5-ethyl -2-pyridyl)ethyl]_2,4-thiazolidinone. RS-4 is (+/-)-ethyl·2-carbamoylthio (carbamoyltio)-3-[4-[2-(5-ethyl-2-yl) ethoxy]benzene Base _] propionate. RS-5 is ethyl-3-p-[2-(5-ethyl-2-pyridyl)ethoxy]phenylpropionate* The final polished bond is packaged in 100 cc HDPE The bottle contains 2 grams of SORB-IT® desiccant canister and is at 40 1361070 ° C, 75 ° /. Accelerated stability conditions for relative humidity. After storage, the final polished tablet is tested in a USP device, type 1 at 100 rpm, pH 2. 〇, HC1-0.3M KC1 buffer. The following basic information on the dissolution of glitazone hydrochloride is shown below: Noodles in the pits of the pits * 10 minutes 38% 20 minutes 73% 30 minutes 92% 45 minutes 101 % by using 5 micron, 120A, 4 YMC -ODS-AQ column; mobile phase is
冰醋酸（25 : 25 : 1) /分鐘；管柱溫度為 .6 X 250 毫米之 0-1Μ乙酸錄緩衝液：乙腈： :注射體積為40微升；流速為〇·7毫升 25C且UV偵測器波長為269奈米之Glacial acetic acid (25: 25: 1) / min; column temperature is .6 X 250 mm 0-1 Μ acetic acid recording buffer: acetonitrile: : injection volume is 40 μl; flow rate is 〇 · 7 ml 25 C and UV detection The detector wavelength is 269 nm
HPLC進订測試時，該經儲存之經最後磨光的鍵劑亦含有下 列0比格列酮相關化合物。 時間 含量(％) 0.7 N.D.* 1.0 1.5 0.03 3.4 0.05 1.2 0.02 2.8 0.04 名稱 RS-1 吡格列酮 RS-2 RS-3 RS-4 RS-5 N.D. =未測得 1361070 前述本發明之特定較佳且替代實施例係用以闡明本發 明，熟悉此技藝者可對已揭示之具體實施例進行修飾。因 此，隨附之申請專利範圍係涵蓋本發明之所有具體實施例 及在不悖離本發明之精神及範疇下所進行之修飾。The stored final polished bond also contained the following 0 glitazone related compounds during the HPLC sequencing test. Time content (%) 0.7 ND* 1.0 1.5 0.03 3.4 0.05 1.2 0.02 2.8 0.04 Name RS-1 pioglitazone RS-2 RS-3 RS-4 RS-5 ND = not measured 1361070 The specific preferred and alternative implementation of the foregoing invention The invention is set forth to illustrate the invention, and modifications may be made to the specific embodiments disclosed. Therefore, the scope of the appended claims is intended to cover all of the embodiments of the invention
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/777,542 US7959946B2 (en) | 2002-09-20 | 2004-02-12 | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
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| TWI361070B true TWI361070B (en) | 2012-04-01 |
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| MY (1) | MY146095A (en) |
| TW (1) | TWI361070B (en) |
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