1233363 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（3 ) 釋放藥劑，以便在病患淸醒前達到藥效，這具有顯著的便 利性。處方能合適的包括複數劑量，其能被服用後於一預 定的時段舒緩之後即刻跟隨著下一次的舒緩。在風濕性關 節炎的情況就能以這種處方治療，當病患醒來時遭受風濕 性關節炎而感到難以行動，所以提供一種處方能在晚間服 用且藥劑能在隔日早晨釋放，以便方便的在病患淸醒前達 到藥效。處方能合適的包含複數劑量，其能經服用後整天 提供直接的舒緩加上隔日早晨的舒緩。 需要一種在預定釋放之後能再釋放藥劑的延遲釋放處方 ，更佳的是藥劑的延遲釋放能和/或預期症狀的發生或再 發生相吻合而治療。 本發明根據以上討論的一或多個問題，已經發現包含分 解劑於固體劑量單位之核心中、外部環繞由一種能滲透的 非水溶性聚合物及至少50重量％之助流劑所組成之半透 膜，令人驚奇地提供了所期望的延遲性及隨後的釋放輪廓 。新穎處方能在大量的pH下以單獨的方式來延遲釋放，在 延遲期間之後藥劑即能立即釋放。 延遲和隨後的釋放輪廓可利用選擇組合物和/或半透膜 的厚度和/或組合物和/或核心所包含分解劑的量來巧妙 處理。核心中分解劑的排列也適合影響延遲和隨後的釋放 輪廓，例如它能包含作爲隔離核心的外層。 本發明第一狀態爲對於藥劑之延遲釋放提供一固體劑量 單位，包含： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明（+) a ) —種包含藥劑及至少一種分解劑之核心 b )核心外層包圍著一半透膜，其由一種能滲透的非水溶 性聚合物及至少50重量％之助流劑所組成。 固體劑量單位能以所知的先前技術合適的製成九劑、小 錠劑、顆粒劑、錠劑等，藥劑能藉由任何適合的傳統方法 包含於單位中，例如它能在核心物質中被結合或是用於種 核的外衣，包含或不包含其他製成單位之構成要素，藥劑 和分解劑能包括如核心之隔離層或混合後置於核心。 單位藥劑較佳是當它們做活體外顯示之擬態腸液的最小 劑量藥劑爲直到至少四小時後才顯示釋放，而且實質上在 24小時後顯示所有的藥劑皆已釋放。較佳的具體藥劑爲那 些最小劑量藥於活體外顯示之擬態腸液中至少釋放至6小 時之後。本發明進一步的具體藥劑爲那些提供最小劑量藥 在活體外顯示之擬態腸液中，分別地釋放至至少8、9、 1 〇、11及1 2小時之後，每個具體藥劑中，實質上所有藥 劑在活體外顯示之擬態腸液中皆釋放至24小時之後，更佳 的爲實質上所有藥劑在活體外顯示之擬態腸液中皆釋放 至22小時之後。 活體外溶解輪廓能由已知技術所決定，例如使用USP設 備IV，以16莫耳/分鐘之速率注入溫度37 °C，pH 6.5之 0 · 5 Μ磷酸鹽緩衝液中，結果應依測量方法而只有些許改 變〇 理論上於活體外顯示之擬態腸液中應能計算出藥劑 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） I m0------------------訂---------—r----- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（5) 1 00%的釋放，然而，事實上通常無法達到，即使經過很 長一段時間也無法計算出超過如85 %的藥劑。這部分歸於 偵測機器原本的限制，而且事實上不可避免的藥劑會被其 他的化學物質所破壞，所以無法偵測或少部分經很長一段 時間才釋放，故重點在於”實質上所有的藥劑已經被釋放” ，所以應該著眼於藥劑釋放量沒有進一步的增加’例如當 觀察到進一步釋放之最小量時。換言之，所有其他的測量 方法爲以百分率法來計算處方中所含所有的藥。 於本發明其他具體藥劑中，藥劑中低於1 〇%會在活體外 顯示之擬態腸液中於4小時之後被釋放，至少30%於10 小時之後顯示被釋放，且至少70%於24小時之後顯示被 釋放，較佳的爲至少70%於20小時之後顯示被釋放。這 些測量是漸增的，換言之，所謂”於…後被釋放”是指所有 釋放藥劑的量於起始時間被計算，換言之，於4、1 〇或20 小時之後，在活體外所顯示之擬態腸液。 於進一步具體藥劑中，藥劑中低於5%會在活體外顯示 之擬態腸液中於4小時之後被釋放，至少35%於1〇小時之 後顯示被釋放，且至少75%於24小時之後顯示被釋放’ 較佳的爲至少75%於20小時之後顯示被釋放。進一步具 體藥劑中，藥劑中低於5%會在活體外顯示之擬態腸液中 於4小時之後被釋放，至少40%於1 0小時之後顯示被釋放 ，且至少80%於20小時之後顯示被釋放。 於本發明其他具體藥劑中，藥劑中低於1 0%會在活體外 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 12----------in------------I"r I--- (請先間讀背面之注意事項存填寫本頁) 經濟部智慧財產局員工消費合作社印製 1233363 Α7 Β7 五、發明說明（ο 顯示於6小時之後釋放，至少30%於1 〇小時之後釋放’且 至少7 0 %於2 4小時之後釋放，較佳的爲至少7 〇 %於2 〇小 時之後釋放。進一步具體藥劑中’藥劑中低於5%會在活 體外顯示於6小時之後被釋放，至少35%於1 0小時之後釋 放，且至少7 5 %於2 0小時之後釋放。進一步具體樂劑中 ，藥劑中低於5%會在活體外顯示於6小時之後被釋放’ 至少40%於1〇小時之後釋放，且至少80%於20小時之後 釋放。 於本發明還有其他具體藥劑中，藥劑中低於10%會在活 體外顯示於8小時之後被釋放’至少30%於1 2小時之後釋 放，且至少70%於24小時之後釋放’較佳的爲至少70%於 20小時之後釋放。進一步具體藥劑中，藥劑中低於5%會在 活體外顯示於8小時之後釋放’至少3 5%於丨2小時之後釋 放，且至少7 5 %於2 0小時之後釋放。進一步具體藥劑中 ，藥劑中低於5 %會在活體外顯示釋放至8小時之後’至 少40%釋放至1 〇小時之後且至少80%釋放至20小時之後 〇 於本發明還有其他具體藥劑中，藥劑中低於1 0%會在活 體外顯示於1 〇小時之後被釋放，至少30%於14小時之後 釋放，且至少70%於24小時之後顯示被釋放’較佳的爲 至少70%於22小時之後釋放。進一步具體藥劑中’藥劑 中低於5 %會在活體外顯示於1 0小時之後釋放’至少3 5 % 於14小時之後釋放，且至少75%於22小時之後釋放。進 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） —i------------------訂-------- (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1233363 A7 _____B7 _________ 五、發明說明（1 ) 一步具體藥劑中，藥劑中低於5%會在活體外顯示於1 〇小 時之後釋放，至少40%於14小時之後釋放，且至少8〇%於 2 2小時之後釋放。 本發明還有其他具體藥劑中，藥劑中低於1 0%會在活體 外顯示於12小時之後釋放，至少30%於16小時之後釋放 ，且至少70%於24小時之後釋放。進一步具體藥劑中’ 藥劑中低於5%會在活體外顯示於1 2小時之後釋放’至少 35%於16小時之後釋放，且至少75%於24小時之後釋放 。進一步具體藥劑中，藥劑中低於5 %會在活體外顯币於 1 2小時之後釋放，至少40%於1 6小時之後釋放，且至少 80%於24小時之後釋放。 合適的分解劑包括有交聯羧甲醚纖維素鈉、交聯聚嫌 酮、澱粉羥乙酸鈉等，這些物質導致服用量單位的膨脹及 分解。 半透膜由一種能滲透的非水溶性聚合物及至少50重量％ 之助流劑所組成。助流劑之重量計數至少爲膜之總重的50% 。半透膜可隨意的由更多的成分所組成’但較佳的具體藥 劑僅爲能滲透的非水溶性聚合物與助流劑所組成之膜。 半透膜較佳的由至少5 5%的助流劑所組成’更佳的爲含 60%的助流劑，最佳的爲含65%的助流劑，本發明特別之 具體藥劑所含之半透膜，其由至少66%所組成。 合適的助流劑包括有滑石、二氧化矽、高嶺土、單硬脂 酸甘油酯、硬脂酸金屬鹽，如硬脂酸鎂、二氧化鈦及澱粉 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------^--------- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（友） 。較佳的助流劑爲滑石、二氧化矽及高嶺土，最佳的助流 劑爲滑石。醫藥組合物經常由至少30%助流劑（如滑石） 所組成，然而本發明中助流劑之功能完全不同於以往的功 能，助流劑大量的包含於半透膜中，其影響了膜之機制和 物理性質。適合的聚合物包括甲基丙烯酸聚合物，如兒札 吉特類（Eudragi t s )、加成聚合物，如PVAP、PVP及PVA 、纖維素衍生物，如醋酸纖維素、乙基纖維素、醋酸纖維 素琥珀酸鹽、醋酸纖維素酞酸鹽、羥丙基甲基纖維素及合 適的樹脂，如蟲膠。較佳的聚合物爲甲基丙烯酸衍生物、 乙基纖維素及醋酸纖維素，最佳的聚合物爲甲基丙烯酸聚 合物，如兒札吉斯、尤其是兒札吉特RS，而膜最好不含增 塑劑。 半透膜令人驚奇的能夠分解劑物質膨脹的壓力直到破裂 時的臨界點，然後開始藥劑的釋放。 單位藥釋放藥劑最好以非滲透性、大量pH値獨立方式， 單位藥最好在胃的環境下缺少保護，例如缺少腸衣。單位 藥最好缺少滲透調節劑。 單位藥劑尤其適合控制質子泵浦抑制劑，較佳的爲蘭索 普拉容、盤妥普拉容、奧美普拉容、普耳普拉容等，它們 能包含於處方，適合治療十二指腸潰瘍、胃液型潰瘍和反 流性食道炎，單位藥劑也適合控制其他藥劑之傳遞，例如 照例地支配複數劑量的藥或當時間爲以上討論的重點原 因時。藥劑可被包含於單位藥劑內，包括如質子泵浦抑制 -1 0 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------1—--------訂-------- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 A7 ___B7___ 五、發明說明（/0 ) 於十小時後，活體外顯示之擬態腸液中至少藥的50%被釋 放，較佳的爲至少55%被釋放，更佳的爲至少60%被釋放 及，最佳的爲至低於65%被釋放。這些每一個具體藥劑於 24小時後，活體外顯示之擬態腸液中至少藥的70%被釋放 ，較佳的爲至少75%被釋放，更佳的爲至少80%被釋放。 本發明一個具體藥劑中，於活體外顯示低於藥的1 〇%於 四小時後釋放，至少30%於十小時後釋放，及至少70%於 20小時後釋放。進一步的具體藥劑中，於活體外顯示低於 藥的5%於四小時後釋放，至少35%於十小時後釋放，及 至少75%於20小時後釋放。進一步的具體藥劑中，於活 體外顯示低於藥的5%於四小時後釋放，至少40%於十小 時後釋放，及至少80%於20小時後釋放。 本發明其他具體藥劑中，於活體外顯示低於藥的1 〇%於 六小時後釋放，至少30%於十小時後釋放，及至少70%於 20小時後釋放。進一步的具體藥劑中，於活體外顯示低於 藥的5%於六小時後釋放，至少35%於十小時後釋放，及 至少75%於20小時後釋放。進一步的具體藥劑中，於活 體外顯示低於藥的5%於六小時後釋放，至少40%於十小 時後釋放，及至少80%於20小時後釋放。 本發明還有其他具體藥劑中，於活體外顯示低於藥的1 〇% 於8小時後釋放，至少30%於12小時後釋放’及至少7〇% 於20小時後釋放。進一步的具體藥劑中，於活體外顯示低 於藥的5%於8小時後被釋放，至少35%於1 2小時後釋放 -1 2- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） I-------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（丨丨） ，及至少75%於20小時後釋放。進一步的具體藥劑中， 於活體外顯示低於藥的5%於8小時後釋放，至少40%於 十小時後釋放，及至少80%於20小時後釋放。 本發明還有其他具體藥劑中，於活體外顯示低於藥的1 〇% 於10小時後釋放，至少30%於14小時後釋放，及至少70% 於22小時後釋放。進一步的具體藥劑中，於活體外顯示低 於藥的5%於10小時後釋放，至少35%於14小時後釋放 ，及至少75%於22小時後釋放。進一步的具體藥劑中， 於活體外顯示低於藥的5%於1 0小時後釋放，至少40%於 14小時後釋放，及至少80%於22小時後釋放。 本發明還有其他具體藥劑中，於活體外顯示低於藥的1 〇% 於1 2小時後釋放，至少30%於1 6小時後釋放，及至少70% 於24小時後釋放。進一步的具體藥劑中，於活體外顯示低 於藥的5%於12小時後釋放，至少35%於16小時後釋放 ，及至少75%於24小時後釋放。進一步的具體藥劑中， 於活體外顯示低於藥的5%於1 2小時後釋放，至少40%於 16小時後釋放，及至少80%於24小時後釋放。 本發明第三個方向提供一種口服的配方來控制藥的釋放 ，其由上述固體劑量單位所組成’這些包含用來控制藥的 釋放之口服配方，其由含藥劑之固體劑量單位的第一族群 與由含藥劑之固體劑量單位的第二族群所組成，其中第一 族群由單位藥劑所組成，其活體外溶解輪廓全部呈現於下 列在活體外顯示之擬態腸液中： -1 3 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） il·!——f—— (請先閱讀背面之注意事項再填寫本頁) — — — — — — — — — 1233363 經濟部智慧財產局員工消費合作社印製 A7 __B7 _ 五、發明說明（) i )兩小時顯示後包含於第一族群之所有藥劑中至少60%被 釋放。 及i i )三小時後顯示包含於第一族群之所有藥劑的至少 80%被釋放。 且第二族群由上述單位藥劑所組成。 第一族群所組成的單位藥劑較佳的如兩小時後於活體外 顯示之擬態腸液中，包含於第一族群之所有藥劑中至少65% 被釋放，更佳的爲至少70%被釋放，最佳的爲至少75%被 釋放。第一族群所組成的單位藥劑較佳的如三小時後於活 體外顯示之擬態腸液中，包含於第一族群之所有藥劑中至 少80%被釋放，更佳的爲至少85%被釋放，最佳的爲至少 90%被釋放。 本發明的單位藥劑能包含任何適合之口服配方，如錠劑 、膠囊極爲膠囊。其他的實例顯然爲熟悉此技術者可行， 如合適的賦形劑及包含於處方劑內。 第一族群的單位藥劑較佳的釋放藥劑是當處方或單位藥 由胃通過至小場所造成的pH値改變時，這可由已知方法達 成，如在單位藥外覆蓋一層腸衣，當十二指腸環境之pH 値達到改變，則會引起腸衣的溶解及藥劑的釋放。適合腸 衣的物質可依先前技藝製備，如醋酸纖維素酞酸鹽、羥丙 基甲基纖維素酞酸鹽，較佳的物質爲兒札吉特S1 00、兒札 吉特L 100、兒札吉特L 100.55及兒札吉特L30D-55，最 佳的爲兒札吉特L30D-55。 -1 4- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂 --------I 卜 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1233363 A7 ______B7___ 五、發明說明Ο3 ) 處方適合質子泵浦抑制劑的多相傳遞，較佳的爲蘭索普 拉容、盤妥普拉容、奧美普拉容、普耳普拉容等，這些處 方適合治療十二指腸潰瘍、胃液型潰瘍和反流性食道炎， 處方也適合其他藥劑傳遞之調整，例如照例地支配複數劑 量的藥或爲以上討論原因所持續不變的釋放處方。藥劑可 被包含於處方內，包括如質子泵浦抑制劑、抗發炎劑、抗 高血壓劑、抗生素、賀爾蒙製劑及對內分泌有活性之製劑 。包含於單位藥劑的第一及第二族群之藥劑可以不同或 相同，較佳的處方是包含於第一及第二族群內爲相同的藥 劑，但包含於第一及第二族群之藥劑量可以不同或相同。 單位藥劑可合適的被混入傳遞系統，其提供了藥劑的多 項傳遞，換言之其由單劑量處方中提供至少兩項傳遞，進 一步的傳遞相能藉由包含固體劑量單位的先前族群在延 遲的不同時段後適合的傳遞藥劑。兩相之間隔時間能藉由 單位藥劑的組成之選擇被巧妙處理，換言之，即是組成物 的選擇和/或半透膜的厚度和/或組成物和/或包含於核心 之分解劑的量和/或在每一族群之核心中分解劑的排列。 處方較佳的爲適合每天施予一次，它們較佳的適合控制 胃中pH値超過24小時，特佳的處方爲那些能控制胃中PH 値超過24小時且避免在此期間pH値低於4.0。 本發明亦提供一種由適合製備上述之固體劑量單位之可 滲透的非水溶性聚合物及至少50重量％助流劑所組成之 組成物，組成物更佳的由至少5 5重量％助流劑所組成’甚 -1 5 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂---------« (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1233363 A7 _B7 五、發明說明（肸） 至更佳的由至少60重量％助流劑所組成，最佳的由至少66 重量％助流劑所組成。較佳的助流劑物質包括滑石、二氧 化矽、高嶺土、單硬脂酸甘油酯、硬脂酸鎂及其他硬脂酸 金屬鹽，最佳的助流劑爲滑石。聚合物可合適的爲甲基丙 烯酸聚合物，如兒札吉特。 本發明依然進一步的提供一種如上所述製備固體劑量單 位之方法，其組成爲由藥劑組成之包覆核心與分解劑及由 可滲透的非水溶性聚合物組成之組成物及至少50重量％助 流劑。本發明亦提供如上所述製備口服處方之方法，其由 如上所述之固體劑量單位與合適的組成物聯合後，提供的 小顆粒劑、小錠劑、顆粒劑或錠劑。 現將以下列實施例作爲參考來例證本發明，並僅以舉例 方式。 圖示 第1圖爲顯示在pH 6 . 5磷酸鹽緩衝液中，實施例1之A型 蘭索普拉容小顆粒的活體外釋放輪廓。 第2圖爲顯示在PH 6.5磷酸鹽緩衝液中，實施例1之B型 蘭索普拉容小顆粒的活體外釋放輪廓。 第3圖爲顯示在PH 6.5磷酸鹽緩衝液中，實施例2之蘭索 普拉容A及B的活體外釋放輪廓。 第4圖爲顯示實施例2之蘭索普拉容A及B的活體外釋放 輪廓。 第5圖爲顯示在PH 6 . 5磷酸鹽緩衝液中，實施例3之單蘭 -16- 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） ίί------曹—— ί請先閱讀背面之注意事項再填寫本頁) 訂---------·# 經濟部智慧財產局員工消費合作社印製 1233363 A7 _____B7_ 五、發明說明（15 ) 索普拉容小錠劑的活體外釋放輪廓。 實施例1 :包含蘭索普拉容小顆粒之製備 將糖球裝於蓋特砂糖成粒機上，並用羥丙基甲基纖維素 爲結合溶液噴於異丙醇，同時將羥丙基甲基纖維素（低替 代）、碳酸鎂、蘭索普拉容、蔗糖及玉米澱粉各粉末混合 ，提供具下列組成成分之包含藥劑的核心：1233363 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (3) Release the medicament so as to achieve the drug effect before the patient wakes up, which has significant convenience. The prescription can suitably include multiple doses, which can be soothed for a predetermined period of time immediately following the next soothing after being taken. In the case of rheumatoid arthritis, it can be treated with this prescription. When patients wake up with rheumatoid arthritis and feel difficult to move, a prescription can be taken at night and the medicine can be released in the morning the next day for convenience. The effect is achieved before the patient wakes up. The prescription can suitably include multiple doses that provide immediate relief throughout the day after taking it, plus relief in the morning the next day. There is a need for a delayed release prescription that can re-release the medicament after the scheduled release, and more preferably, the delayed release of the medicament is consistent with the occurrence or recurrence of the expected symptoms for treatment. According to one or more of the problems discussed above, the present invention has been found to include a disintegrating agent in the core of a solid dosage unit, the outer periphery of which is composed of a permeable non-water-soluble polymer and at least 50% by weight of a glidant. Permeable membranes surprisingly provide the desired retardation and subsequent release profile. The novel formulation can delay the release in a single manner at a large number of pH, and the drug can be released immediately after the delay period. The delayed and subsequent release profile can be neatly handled by selecting the thickness of the composition and / or semi-permeable membrane and / or the amount of disintegrating agent contained in the composition and / or core. The arrangement of the disintegrating agents in the core is also suitable for influencing the delay and subsequent release profile, for example it can contain an outer layer as a barrier core. The first state of the present invention is to provide a solid dosage unit for the delayed release of a medicament, including: The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- order --- ------ (Please read the notes on the back before filling this page) 1233363 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention (+) a) — a kind of medicine containing at least one decomposition agent The core b) The core outer layer surrounds a semi-permeable membrane, which is composed of a permeable water-insoluble polymer and at least 50% by weight of a glidant. The solid dosage unit can be suitably prepared into nine units, small lozenges, granules, lozenges, etc. according to the known prior art. The medicine can be contained in the unit by any suitable conventional method, for example, it can be contained in the core substance. The outer clothing that is combined or used for the seed nucleus, contains or does not contain the constituent elements of other manufactured units, and the medicament and decomposer can include an isolation layer such as the core or be placed in the core after mixing. The unit doses are preferably such that the minimum doses of the mimic intestinal fluids displayed in vitro are not released until at least four hours have elapsed, and substantially all the agents have been released after 24 hours. Preferred specific medicaments are those that are released at least 6 hours after the smallest dose of the mimic intestinal fluid shown in vitro. Further specific agents of the present invention are those mimetic intestinal fluids that provide the minimum dose of drugs to be displayed in vitro, and are released to at least 8, 9, 10, 11, and 12 hours, respectively. After each specific agent, substantially all agents The mimic intestinal fluid displayed in vitro is released to 24 hours later, and it is more preferable that substantially all the agents are released to the mimic intestinal fluid displayed in vitro after 22 hours. The in vitro dissolution profile can be determined by known techniques. For example, using USP equipment IV, inject at a rate of 16 mol / min into a 37 ° C, pH 6.5 0 · 5 M phosphate buffer solution. The results should be based on the measurement method. There are only a few changes. Theoretically, the mimic intestinal fluid displayed in vitro should be able to calculate the medicine. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) I m0 --------- --------- Order ---------- r ----- (Please read the notes on the back before filling this page) 1233363 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (5) 100% release, however, it is usually not achieved in fact, and even after a long period of time, it is impossible to calculate more than 85% of the drug. This part is due to the original limitation of the detection machine, and in fact the inevitable medicament will be destroyed by other chemicals, so it cannot be detected or a small part will be released for a long time, so the focus is on "essentially all medicaments Already released ", so one should look at no further increase in the amount of agent released, for example when a minimum amount of further release is observed. In other words, all other measurement methods use the percentage method to calculate all medicines contained in the prescription. In other specific agents of the present invention, less than 10% of the agents are released in the mimic intestinal fluid displayed in vitro after 4 hours, at least 30% are shown to be released after 10 hours, and at least 70% are released after 24 hours The display is released, preferably at least 70% after 20 hours. These measurements are incremental, in other words, "released after" means that the amount of all released agents is calculated at the start time, in other words, the mimicry displayed in vitro after 4, 10, or 20 hours Intestinal fluid. In further specific medicaments, less than 5% of the medicament will be released after 4 hours in mimic intestinal fluid displayed in vitro, at least 35% will be released after 10 hours, and at least 75% will be displayed after 24 hours Release 'is preferably at least 75% showing release after 20 hours. In further specific agents, less than 5% of the agents will be released after 4 hours in mimic intestinal fluid displayed in vitro, at least 40% will be released after 10 hours, and at least 80% will be released after 20 hours. . In other specific medicaments of the present invention, less than 10% of the medicaments will be applied to Chinese paper (CNS) A4 specifications (210 X 297 mm) in vitro on the paper scale. 12 ---------- in ------------ I " r I --- (Please read the precautions on the back and fill in this page first) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1233363 Α7 Β7 V. Description of the invention (Ο is shown to release after 6 hours, at least 30% is released after 10 hours' and at least 70% is released after 24 hours, preferably at least 70% is released after 20 hours. Further specifically in the medicament 'Less than 5% of the medicament will be released in vitro after 6 hours, at least 35% will be released after 10 hours, and at least 75% will be released after 20 hours. Further specific medicaments, medicaments are low 5% will be shown to be released in vitro after 6 hours' at least 40% are released after 10 hours, and at least 80% are released after 20 hours. In other specific agents of the present invention, the agent is less than 10 % Will be released in vitro after 8 hours' at least 30% will be released after 12 hours, and at least 70% Release after 24 hours 'is preferred to release at least 70% after 20 hours. In further specific agents, less than 5% of the agents will be shown to release after 8 hours in vitro' at least 3 5% will be released after 2 hours And at least 75% will be released after 20 hours. In further specific agents, less than 5% of the agent will be shown to release in vitro after 8 hours' release of at least 40% after 10 hours and at least 80% release After 20 hours, in the present invention and other specific agents, less than 10% of the agents will be released in vitro after 10 hours, at least 30% will be released after 14 hours, and at least 70% will be released in 24 hours. It is shown to be released later, preferably at least 70% is released after 22 hours. Further specifically, in medicine, 'less than 5% of the medicine will be released in vitro after 10 hours' and at least 35% will be released after 14 hours. And at least 75% will be released after 22 hours. The size of this paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) —i ----------------- -Order -------- (Please read the notes on the back before filling this page) Economy Printed by the Intellectual Property Bureau's Consumer Cooperatives 1233363 A7 _____B7 _________ V. Description of the Invention (1) In a specific medicine, less than 5% of the medicine will be released in vitro after 10 hours and at least 40% will be released after 14 hours And at least 80% will be released after 22 hours. In other specific agents of the present invention, less than 10% of the agents will be released in vitro after 12 hours, and at least 30% will be released after 16 hours, and At least 70% are released after 24 hours. Further specifically, in the pharmaceutical agent, "less than 5% of the pharmaceutical agent will be released in vitro after 12 hours", at least 35% will be released after 16 hours, and at least 75% will be released after 24 hours. In further specific agents, less than 5% of the agents will be released in vitro after 12 hours, at least 40% will be released after 16 hours, and at least 80% will be released after 24 hours. Suitable disintegrants include croscarmellose sodium, croscarmone, sodium starch glycolate, etc. These substances cause swelling and decomposition of the dosage unit. The semi-permeable membrane is composed of a permeable water-insoluble polymer and at least 50% by weight of a glidant. The weight count of the glidant is at least 50% of the total weight of the film. The semi-permeable membrane can optionally be composed of more components', but the preferred specific drug is only a membrane composed of a permeable, water-insoluble polymer and a glidant. The semi-permeable membrane is preferably composed of at least 55% of the glidant. More preferably, it contains 60% of the glidant, and most preferably contains 65% of the glidant. The specific agent of the present invention contains Semi-permeable membrane, which consists of at least 66%. Suitable glidants include talc, silica, kaolin, glyceryl monostearate, metal stearates, such as magnesium stearate, titanium dioxide, and starch. This paper applies Chinese National Standard (CNS) A4 specifications ( 210 X 297 mm) -------- ^ --------- (Please read the notes on the back before filling out this page) 1233363 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 5. Description of invention (friend). The preferred glidants are talc, silica and kaolin, and the best glidants are talc. Pharmaceutical compositions are often composed of at least 30% glidants (such as talc). However, the function of the glidant in the present invention is completely different from that of the past. Mechanism and physical properties. Suitable polymers include methacrylic polymers, such as Eudragits, addition polymers, such as PVAP, PVP and PVA, cellulose derivatives, such as cellulose acetate, ethyl cellulose, acetic acid Cellulose succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose and suitable resins such as shellac. The preferred polymers are methacrylic acid derivatives, ethyl cellulose, and cellulose acetate. The most preferred polymers are methacrylic polymers, such as Erzagits, especially Erzagit RS. Good without plasticizers. The semi-permeable membrane is surprisingly capable of breaking down the pressure at which the agent substance swells up to a critical point at the time of rupture, and then begins the release of the agent. The unit drug release agent is preferably in a non-osmotic, bulk pH-independent manner, and the unit drug is preferably lacking protection in the environment of the stomach, such as a casing. The unit drug preferably lacks an osmolyte. Unit medicaments are particularly suitable for controlling proton pump inhibitors, preferably lansopramine, pantopramine, omepramine, propulon, etc., which can be included in the prescription and suitable for the treatment of duodenal ulcers Gastric ulcers and reflux esophagitis. Unit medicines are also suitable for controlling the delivery of other medicines, such as the usual control of multiple doses of medicines or when time is the key cause discussed above. Pharmacy can be included in the unit pharmacy, including, for example, proton pump suppression-1 0-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------- 1 ----- ----- Order -------- (Please read the notes on the back before filling out this page) 1233363 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ___B7___ V. Description of Invention (/ 0) After hours, at least 50% of the drug in the mimic intestinal fluid displayed in vitro is released, preferably at least 55% is released, more preferably at least 60% is released, and most preferably less than 65% is released . After 24 hours of each of these specific agents, at least 70% of the drug in the mimic intestinal fluid shown in vitro is released, preferably at least 75% is released, and even more preferably at least 80% is released. In a specific agent of the present invention, less than 10% of the drug is released in vitro after four hours, at least 30% is released after ten hours, and at least 70% is released after 20 hours. In further specific agents, less than 5% of the drug is released in vitro after four hours, at least 35% is released after ten hours, and at least 75% is released after 20 hours. In further specific agents, less than 5% of the drug in vitro is released after four hours, at least 40% is released after ten hours, and at least 80% is released after 20 hours. Among other specific agents of the present invention, less than 10% of the drug is released in vitro after six hours, at least 30% is released after ten hours, and at least 70% is released after 20 hours. In further specific agents, less than 5% of the drug is released in vitro after six hours, at least 35% is released after ten hours, and at least 75% is released after 20 hours. In further specific agents, less than 5% of the drug in vitro is released after six hours, at least 40% is released after ten hours, and at least 80% is released after 20 hours. Among other specific agents of the present invention, less than 10% of the drug in vitro is released after 8 hours, at least 30% is released after 12 hours' and at least 70% is released after 20 hours. In further specific medicaments, less than 5% of the drug showed in vitro is released after 8 hours, and at least 35% is released after 12 hours. 1 2- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) I ------------------- Order --------- (Please read the notes on the back before filling this page) 1233363 Economy A7 B7 printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau V. Invention Description (丨 丨), and at least 75% will be released after 20 hours. In further specific agents, less than 5% of the drug in vitro is released after 8 hours, at least 40% is released after 10 hours, and at least 80% is released after 20 hours. Among other specific agents of the invention, less than 10% of the drug is released in vitro after 10 hours, at least 30% is released after 14 hours, and at least 70% is released after 22 hours. In further specific agents, less than 5% of the drug in vitro is released after 10 hours, at least 35% is released after 14 hours, and at least 75% is released after 22 hours. In further specific agents, less than 5% of the drug in vitro is released after 10 hours, at least 40% is released after 14 hours, and at least 80% is released after 22 hours. Among other specific agents of the present invention, less than 10% of the drug is released in vitro after 12 hours, at least 30% is released after 16 hours, and at least 70% is released after 24 hours. In further specific agents, 5% showing less than the drug in vitro is released after 12 hours, at least 35% is released after 16 hours, and at least 75% is released after 24 hours. In further specific agents, less than 5% of the drug in vitro is released after 12 hours, at least 40% is released after 16 hours, and at least 80% is released after 24 hours. A third aspect of the present invention provides an oral formulation to control drug release, which consists of the solid dosage units described above. These include oral formulations for controlling drug release, which are comprised of a first group of solid dosage units containing pharmaceuticals It is composed of a second group of solid dosage units containing medicaments. The first group is composed of unit medicaments. The in vitro dissolution profiles are all presented in the following mimic intestinal fluid shown in vitro: -1 3-paper size Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) il ·! —— f—— (Please read the precautions on the back before filling this page) — — — — — — — — — 1233363 Ministry of Economy Wisdom Printed by A7 __B7 _ from the Consumer Cooperatives of the Property Bureau. 5. Description of the invention () i) At least 60% of all the medicines contained in the first group were released after two hours of display. And i i) after three hours showed that at least 80% of all agents contained in the first group were released. And the second group is composed of the above-mentioned unit medicine. The unit medicament composed of the first group is preferably the mimic intestinal fluid displayed in vitro after two hours. At least 65% of all the medicaments contained in the first group are released, and more preferably at least 70% is released. Preferably at least 75% are released. The unit medicament composed of the first group is preferably the mimic intestinal fluid displayed in vitro after three hours. At least 80% of all the medicaments contained in the first group are released, and more preferably at least 85% is released. Preferably at least 90% are released. The unit medicament of the present invention can contain any suitable oral formulation, such as lozenges, capsules, and capsules. Other examples are obviously feasible for those skilled in the art, such as suitable excipients and included in prescriptions. The first group of unit medicaments is preferably released when the pH of the prescription or unit medicament changes from the stomach to a small place. This can be achieved by known methods, such as covering a layer of casing around the unit medicament. Changes in pH 値 will cause the casing to dissolve and release the agent. Substances suitable for casing can be prepared according to the prior art, such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and the preferred substances are Erzagit S100, Erzagit L 100, Erzagit Jitter L 100.55 and Erzagit L30D-55, the best is Erzagit L30D-55. -1 4- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------------- Order ------- -I (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1233363 A7 ______B7___ V. Description of the invention 〇3) The prescription is suitable for multi-phase delivery of proton pump inhibitors Lansopram, Pantopram, Omeprazam, and Promrazam, etc. These prescriptions are suitable for the treatment of duodenal ulcers, gastric ulcers and reflux esophagitis. The prescriptions are also suitable for the delivery of other drugs Adjustments, such as the usual dosing of multiple doses of a drug or the release of a prescription that persists for the reasons discussed above. Medicaments can be included in prescriptions, including, for example, proton pump inhibitors, anti-inflammatory agents, antihypertensive agents, antibiotics, hormone preparations, and preparations that are active on endocrinology. The medicines included in the first and second groups of the unit medicine may be different or the same. The preferred prescription is the same medicines included in the first and second groups, but the doses of the medicines included in the first and second groups can be Different or the same. The unit medicament may be appropriately incorporated into the delivery system, which provides multiple delivery of the medicament, in other words it provides at least two deliveries from a single dose prescription, and further delivery phases can be delayed at different times by the previous population containing the solid dose unit After suitable delivery of medicament. The interval between the two phases can be neatly handled by the choice of the composition of the unit drug, in other words, the choice of the composition and / or the thickness of the semipermeable membrane and / or the amount of the composition and / or the decomposer contained in the core And / or the arrangement of decomposers in the core of each group. The prescriptions are preferably suitable for administration once a day. They are more suitable for controlling pH in the stomach for more than 24 hours. Particularly preferred are those that can control the pH in the stomach for more than 24 hours and avoid pH 値 below 4.0 during this period. . The invention also provides a composition composed of a permeable non-water-soluble polymer and at least 50% by weight of a glidant which is suitable for preparing the solid dosage unit described above, and more preferably at least 55% by weight of a glidant. Composed of 'even-1 5-This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------- Order --- ------ «(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1233363 A7 _B7 V. Description of the invention (肸) To better, at least 60% by weight It is composed of a flow agent, most preferably at least 66% by weight of a glidant. Preferred glidants include talc, silica, kaolin, glyceryl monostearate, magnesium stearate and other metal stearates. The most preferred glidant is talc. The polymer may suitably be a methacrylic polymer such as Erzagit. The present invention still further provides a method for preparing a solid dosage unit as described above, which is composed of a coating core composed of a medicament and a decomposition agent, a composition composed of a permeable non-water-soluble polymer, and at least 50% by weight流 剂。 Flow agent. The present invention also provides a method for preparing an oral prescription as described above, which is a small granule, a small lozenge, a granule or a lozenge provided by combining the solid dosage unit as described above with a suitable composition. The invention will now be illustrated by reference to the following examples, and by way of example only. Figure 1 Figure 1 shows the in vitro release profile of lansoprazole small particles of type A of Example 1 in a pH 6.5 phosphate buffer. Figure 2 shows the in vitro release profile of lansoprazole small particles of type B of Example 1 in a pH 6.5 phosphate buffer. Figure 3 shows the in vitro release profile of lansopramine A and B of Example 2 in a pH 6.5 phosphate buffer. Fig. 4 is a diagram showing the in vitro release profiles of lansoprasone A and B of Example 2. Figure 5 shows the single-lane-16 of Example 3 in a pH 6.5 phosphate buffer solution. The paper size applies the Chinese National Standard (CNS) A4 specification (21〇X 297 mm). --Cao—— ί Please read the notes on the back before filling out this page) Order --------- · # Printed by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economy 1233363 A7 _____B7_ V. Description of the Invention (15) In vitro release profile of Sopramone mini-tablets. Example 1: Preparation of small granules containing lansoprazole. Sugar balls were loaded on a Granat granulator and sprayed with isopropyl alcohol with hydroxypropyl methylcellulose as a binding solution. Base cellulose (low substitution), magnesium carbonate, lansoprazone, sucrose, and corn starch are mixed to provide a pharmaceutical-containing core with the following components:
W/W 糖球 30 ,6 % 羥丙基甲基纖維素 1 _ ,8 % 蘭索普拉容 17 _ ,7 % 碳酸鎂 13 . 2 % 羥丙基甲基纖維素（低替代） 8. 3 % 蔗糖 17 · 7 % 玉米澱粉 10 · 6 % 之後產生包含藥劑之核心被篩選及放迴轉桶中，異丙醇 中的羥丙基甲基纖維素懸浮物及交聯羧甲醚纖維素鈉被 噴於核心上，以提供分解劑覆於具有下列組成成分之核心 上：W / W sugar ball 30, 6% hydroxypropyl methylcellulose 1 _, 8% lansoplam 17 _, 7% magnesium carbonate 13. 2% hydroxypropyl methyl cellulose (low substitution) 8. 3% sucrose 17. 7% corn starch 10. 6% After that, the core containing the drug is screened and placed in a rotating bucket, hydroxypropylmethyl cellulose suspension in isopropanol and croscarmellose sodium Sprayed onto the core to provide a decomposer over the core with the following components:
W/W 交聯羧甲醚纖維素鈉 22.9 % 羥丙基甲基纖維素 5.7 % 含藥劑之核心 71.4% 被分解劑包覆之核心被篩選及置於液化室並用烏斯特法 -1 7 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 A7 _ B7 300 4.9 0 360 18.6 0 . 2 390 29 . 6 2.6 420 39 . 4 6 450 49 . 1 11.5 480 56 . 5 18.7 510 62.4 28 540 67.1 38 . 3 570 70.4 47 600 73 . 7 54.5 630 76.6 61.1 660 79.4 66.7 690 81.8 71.1 720 83 . 9 74.3 750 85 . 7 76.7 780 87.5 78 . 8 810 89. 1 80.6 840 90 . 5 82.3 870 91.8 83.9 900 93 . 0 85 . 8 930 94.2 87 . 3 960 95.4 88 . 6 這些結果於第1及第2圖揭示。 1233363 五、發明說明（θ ) -19- --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1233363 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（ΙΓ) 窨旆例2 ··包含實施例1之及直接釋放小顆粒 之混合物的製備 根據上述方法再提供具下列組成成分之包含藥劑的核心：W / W croscarmellose sodium 22.9% hydroxypropyl methylcellulose 5.7% core with medicament 71.4% core covered with decomposing agent is screened and placed in liquefaction chamber and used Uster method-1 7 -This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------- Order --------- (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _ B7 300 4.9 0 360 18.6 0. 2 390 29. 6 2.6 420 39. 4 6 450 49. 1 11.5 480 56. 5 18.7 510 62.4 28 540 67.1 38. 3 570 70.4 47 600 73. 7 54.5 630 76.6 61.1 660 79.4 66.7 690 81.8 71.1 720 83. 9 74.3 750 85. 7 76.7 780 87.5 78. 8 810 89. 1 80.6 840 90. 5 82.3 870 91.8 83.9 900 93. 0 85 8 930 94.2 87. 3 960 95.4 88. 6 These results are shown in Figures 1 and 2. 1233363 V. Description of the invention (θ) -19- -------- Order --------- (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese national standards ( CNS) A4 specification (210 X 297 mm) 1233363 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (IΓ) · Example 2 · The mixture containing Example 1 and the direct release of small particles The preparation according to the above method further provides a medicament-containing core having the following composition:
W/W 糖球 36. 7 % 經丙基甲基纖維素 0· 5 % 蘭索普拉容 10. 0 % 碳酸鎂 7 . 5 % 經丙基甲基纖維素（低替代） 13 . 3 % 蔗糖 19. 9 % 玉米澱粉 12. 1 % 一下列比例將腸衣增於包含藥劑的核心：W / W Sugar balls 36.7% via propyl methylcellulose 0.5% Lansoplacium 10. 0% magnesium carbonate 7.5% via propyl methyl cellulose (low substitution) 13. 3% Sucrose 19. 9% corn starch 12. 1%-the following ratio will increase the casing to the core containing the agent:
W/W 包含藥劑的核心 81.2 % 兒札吉特L30D-55 12.1 % 滑石 3.8 % 聚乙二醇6000 1 . 2 % 二氧化鈦 1 . 2 % 聚山梨酸酯80 0 . 5 % 導致直接釋放小顆粒劑活體外溶解輪廓使用USP設備IV ，以16莫耳/分鐘知速率注入溫度37 °C，pH 6.5之0.5M 磷酸鹽緩衝液中，直接釋放小顆粒劑之後與實施例1之小 顆粒劑混和，並以下列兩種處方塡入膠囊： -20- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員Η消費合作社印製 A7 B7 五、發明說明（θ) 處方A : A型小顆粒劑與直接釋放小顆粒劑。 處方B : B型小顆粒劑與直接釋放小顆粒劑。 兩種處方劑之活體外溶解輪廓使用USP設備IV，以1 6 莫耳/分鐘知速率注入溫度37 °C，pH 6.5之0.5M磷酸鹽 緩衝液中，結果示於表2。 表2 :包含直接釋放小顆粒劑及延遲釋放小顆 粒劑之處方的溶解輪廓 時間（分） 主藥劑釋放％ 處方A 處方B 60 27 33 120 39 44 180 44 46 240 47 48 300 53 49 360 64 51 420 74 54 480 81 62 540 85 71 600 89 80 660 92 87 720 95 93 780 98 98 這些結果於第3圖揭示。 -21 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------- —訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1233363 A7 ___B7____ 五、發明說明（>) 由18至45歲體重差異10%內的成年男性計算出活體內蘭 索普拉容濃度之平均濃度，利用五種公開方式、隨機性、 安慰劑控制組經過硏究後完成，且包括被實驗者使用包含 相當於總劑量30毫克的約200顆小顆粒劑膠囊治療之結果 ，結果揭示於第4圖。除包含ZotonTM (包覆腸衣之蘭索 普拉容處方）數據之處方A及B，與處方C (包覆腸衣之 處方A小顆粒劑）之外，因這些附加的處方劑之目的乃作 爲比較測試。 實施例3 :含蘭索普拉容延遲釋放小錠劑之製備 乾燥顆粒由蘭索普拉容、乳糖、微晶纖維素及硬脂酸鎂 混和後製備，並乾燥這些顆粒，經由濕的顆粒製備包含碳 酸鎂、交聯聚烯吡酮及羥丙基甲基纖維素之第二顆粒，濕 的顆粒產品經乾燥，於混合乾顆粒產品前碾磨成適當大小 ，所生成的混合物以克林恩LX ( Kilian LX )藥錠碾壓機 之標準工具壓縮爲直徑4毫米的小錠劑。W / W 81.2% core containing medicament L30D-55 12.1% talc 3.8% polyethylene glycol 6000 1.2% titanium dioxide 1.2% polysorbate 80 0.5% resulting in direct release of small granules The in vitro dissolution profile was injected into a 0.5M phosphate buffer solution at 37 ° C, pH 6.5 at a rate of 16 mol / min using a USP device IV at a rate of 16 mol / min. The small granules were directly released and mixed with the small granules of Example 1. The capsules are formulated with the following two prescriptions: -20- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------------ -Order --------- (Please read the notes on the back before filling this page) 1233363 Printed by A7 B7, a member of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperative V. Description of the invention (θ) Recipe A: A type small Granules and direct release small granules. Prescription B: Type B small granules and direct release small granules. The in vitro dissolution profiles of the two prescriptions were injected into a 0.5 M phosphate buffer solution at 37 ° C and pH 6.5 at a rate of 16 mol / min using a USP device IV. The results are shown in Table 2. Table 2: Dissolution profile time (minutes) for the formulations containing the direct-release small granules and delayed-release small granules.% Release of the main drug Formula A Formula B 60 27 33 120 39 44 180 44 46 240 47 48 300 53 49 360 64 51 420 74 54 480 81 62 540 85 71 600 89 80 660 92 87 720 95 93 780 98 98 These results are shown in Figure 3. -21-This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------- --Order --------- (Please read the precautions on the back before filling (This page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1233363 A7 ___B7____ V. Description of the invention (>) The average concentration of lansopramine in vivo was calculated from adult males within 10% of the weight difference between 18 and 45 Using five publicly available, randomized, placebo-controlled groups, the study was completed after investigation, and included the results of treatment by subjects using approximately 200 small granule capsules containing a total dose of 30 mg. Illustration. Except for prescriptions A and B, which contain the data of ZotonTM (the casing-coated lansopramine formulation), and prescription C (the casing-coated formulation A small granules), the purpose of these additional prescriptions is for comparison test. Example 3: Preparation of delayed release small tablets containing lansopramine, dry granules are prepared by mixing lansopramine, lactose, microcrystalline cellulose and magnesium stearate, and drying these particles through wet particles Preparation of second granules containing magnesium carbonate, cross-linked polyketene and hydroxypropyl methylcellulose. The wet granulated product is dried and milled to an appropriate size before mixing the dry granulated product. The standard tool of the Kilian LX ingot compactor is compressed into small tablets with a diameter of 4 mm.
毫克 W/W 碳酸鎂 2.24 7.47 % 交聯羧甲醚纖維素鈉（AcDisol) 1.2 4.00 % 羥丙基甲基纖維素 0.9 3.00 % 蘭索普拉容 3.0 1〇.〇 % 乳糖 1 1.225 37.42 % 微晶纖維素 1 1.225 37.42 % 硬脂酸鎂 0.21 0.70 % -22 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂--------- fw (請先閱讀背面之注意事項再填寫本頁) 1233363 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明) 未包覆之小錠劑依實施例所述以兒札吉特及滑石包覆：Mg W / W magnesium carbonate 2.24 7.47% croscarmellose sodium (AcDisol) 1.2 4.00% hydroxypropyl methylcellulose 0.9 3.00% lansoprane capacity 3.0 10.0% lactose 1 1.225 37.42% micro Crystalline cellulose 1 1.225 37.42% Magnesium stearate 0.21 0.70% -22-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------------- ----- Order --------- fw (Please read the notes on the back before filling out this page) 1233363 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention) Not covered The small tablets are coated with ezazagit and talc as described in the examples:
W/W 兒札吉特RS 7.5% 滑石 15.2 % 未包覆之小錠劑 7 7.3 % 單小錠劑之活體外溶解輪廓使用USP設備I V，以1 6莫 耳/分鐘知速率注入溫度37 °C，pH 6.5之0.5 Μ磷酸鹽緩 衝液中，結果示於表3。 表3 :單小錠劑之溶解輪廓 時間（分） 主藥劑釋放％ 240 0 270 0 300 0 330 0 360 0 390 0 420 4.7 450 29.9 480 30.6 510 48.7 540 54.4 570 58.1 600 60 . 7 -23- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------^--------- (請先閱讀背面之注意事項再填寫本頁) 1233363 A7 五、發明說明（A ) _B7 630 63 , ,1 660 65 , .5 690 67 . ,2 720 69 _ .9 750 12. ,2 780 73 . 7 840 79 . 0 900 81 · 7 960 85 · 1 這些結果於第5圖揭示。 -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -24- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）W / W Gerzagit RS 7.5% Talc 15.2% Uncoated tablets 7 7.3% In vitro dissolution profile of a single tablet using USP equipment IV at a rate of 16 mol / min infusion temperature 37 ° C. The results are shown in Table 3 in 0.5 M phosphate buffer at pH 6.5. Table 3: Dissolution profile time (minutes) of a single tablet,% release of main agent 240 0 270 0 300 0 330 0 360 0 390 0 420 4.7 450 29.9 480 30.6 510 48.7 540 54.4 570 58.1 600 60. 7 -23- this Paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------- ^ --------- (Please read the precautions on the back before filling this page) 1233363 A7 V. Description of the invention (A) _B7 630 63,, 1 660 65, .5 690 67., 2 720 69 _ .9 750 12., 2 780 73. 7 840 79. 0 900 81 · 7 960 85 · 1 These results are revealed in Figure 5. ------------------- Order --------- (Please read the notes on the back before filling out this page) Employees ’Cooperatives, Intellectual Property Bureau, Ministry of Economic Affairs Printed -24- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)