TW393320B - An oral hydrogel control release pharmaceutical tablet - Google Patents

An oral hydrogel control release pharmaceutical tablet Download PDF

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Publication number
TW393320B
TW393320B TW82107572A TW82107572A TW393320B TW 393320 B TW393320 B TW 393320B TW 82107572 A TW82107572 A TW 82107572A TW 82107572 A TW82107572 A TW 82107572A TW 393320 B TW393320 B TW 393320B
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Taiwan
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oral
hydrocolloid
tablet
weight
test
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TW82107572A
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Chinese (zh)
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Kazuhiro Sako
Hiroshi Nakashima
Toyohiro Sawada
Akira Okada
Muneo Fukui
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Yamanouchi Pharma Co Ltd
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Abstract

An oral hydrogel control release pharmaceutical tablet comprises: (1) at least one kind of medicine, (2) additives for water to infiltrate into inside of tablets, (3) high molecular substances for forming hydrogel, said preparation has the abilities to gelatinize completely during staying in the upper alimentary tract, and to release the medicine in the colon of the lower alimentary tract. The preparation of this invention can be dissolved and absorbed well even in the colon and can get the stable control release effect.

Description

經濟部中央標準局員工消費合作社印製 A6 _B6_ 五、發明説明（1 ) 技術領域 本發明為有關能使藥物長時間放出之徐放性製劑β詳 言之，為關不僅在消化管上部，消化管下部之結腸也能 使藥物良好地放出之水膠體徐放性製劑。 背景技術 以往，為使藥物徐放化，提出種種水膠體製劑。例如 ，日本待開昭62-120315號公報提出將藥物以能形成水膠 體之水溶性高分子及腸溶衣基劑予以成形壓縮者，日本 特開昭63-215620號公報提出於由藥物及水溶性高分子 物質而成之核及以水溶性高分子物質為基劑之外層而成 之水膠體製劑，日本特公昭40-2053號公報掲示將藥物 及氣化乙烯高聚合物，必要時加親水性物質而成之持缠 性製劑等。 但這些藥劑均以滯留在1，小腸等消化管上部當中持 缠放出藥物為目的，並不以在結腸等水分少之消化管下 部放出藥物為目的。即在消化管内邊下降邊放出及吸收 藥物之徐放性製劑，其在消化管上部之藥物吸收性及放 出性對生物利用性有很大影蜜，但在結腸受水分少及老 廢内容物等之影鎏，以往認為藥物難放出，而殆無研究 有關藥物放出性（曰藥劑學會第6年會講演鼕旨集（平 成 2 年）,30 頁，Pharia. Tech. Japan 8 ( 1 ), ( 1 9 9 2 ), 4 1 頁 > 0 又藥物本身之生物學半衰期雖也為檢討徐放性製劑時 -3 - (請先閱讀背面之注耷事項再塡"本頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（2 ) (請先閱讀背面之注意事項再塡寫本頁) 之重要因子，但對於藥物本身之半衰期短之藥物，咸認 為難充分徐放化（月刊藥事2 5 ( 1 1 ) , ( 1 9 8 3 ) , 2 9頁）。 發明之掲示 本發明者們研究藥物之徐放化中，發現若滯留在如胃、 小腸在消化管上部時，使水分吸收至藥劑内部而以幾乎 完全凝膠化之狀態向消化管下部移行，則在水分少之結 腸也能放出藥物，終於完成本發明。 即本發明為一種水膠體徐放性製劑，包括⑴至少一種 以上藥物，⑵使水浸入錠劑内部之添加劑，及⑶形成水 膠體之高分子物質，具有滞留消化管上部之胃及小腸當 中製劑幾乎完全凝膠化能力，且在消化管下部之結腸放 出藥物之能力。 在本發明中，所謂製劑幾乎完全凝膠化之狀態，乃指 製劑之約70%，宜約80 %以上呈凝膠化之狀態。 本發明之徐放性製劑因結腸也可當作吸收部位而大幅 延長藥物之吸收時間，故可逹成安定之藥物血中濃度。 亦即本發明製劑因在消化管上部滯留中吸收水分而幾乎 完全凝膠化，邊浸蝕製劑表面而邊往消化管下部移行， 更受浸蝕而持缅放出藥物，故在水分少之結腸也能達成 良好且持缠之藥物吸收。 經濟部中央標準局員工消費合作社印製 本發明之徐放性製劑更詳逑如下。 適用於本發明錠劑之一種以上藥物，只要以徐放化為 目的之藥物卽可，並無待別限定。 -4 - 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6_ 五、發明説明（3 ) 代表性藥物可為如吲哚美洒辛，二氮芬，二氣芬鈉， 可待因，伊布普芬，苯丁松，oxyphenbutasone, mepirizole，阿斯必盡，ethenzamide， acetoaminophen, 安替比林，非那西丁，溴化丁基東莨菪鹼，嗎啡， etonidoline, pentazocin， senoprofen教等消炎，解 熱或止痛藥，如isoniazid,鹽酸ethanbutol等抗結核 藥，如硝酸異山梨糖，硝基甘油，尼非地平，鹽酸巴尼 地平，鹽酸尼卡地平，dipyridamol，anrinone,强·酸 indenol，强酸 hydralazine,甲基多巴，furosemide， spirono]. acton,硝酸 quanethidine，力血平，薄酸 araosulalol等循環器用藥，如鹽酸氣普羅麻秦，鹽酸 amitriptylin, neinonapride, haloperidol ,發酸 moperone, perphenazine, — HY (diazepam), lorazepam， chlorcliazepoxide 等抗精神藥，順丁烯 二酸氣非拉民，强酸diphenhydramine等抗組織藥，如 硝酸t h i a m i n e ,乙酸生育酚，C y c 〇 t i a m i n e，磷酸 P y r i d o x a 1 , c o b a m i d e，抗壊血酸，菸鹺醯胺等維生素 藥，如allopurinol，秋水仙素，probenecid等痛風藥 ,如異戊巴比妥，溴戊醯脲，midazolam,水介氩醛等 催眠饌靜藥，如fluorouracil, cariaofur,鹽酸 aclarubicin, cyclophosphamide , thiotepa等抗惡性 瘤藥，如苯丙醇胺，麻黃素類等抗瘀血藥，乙醒己醯胺 ,胰島素，甲苯丁醯胺等糖尿病藥，如hydrothiazide, -5- (請先閱讀背面之注意事項冉塡寫本頁) -裝. -έ . .缚. 本紙張尺度適用_中國a家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 __ _B6_ 五、發明説明（4 ) polythiazide， triamteren等利尿藥，如 aninophylline ，反丁烯二酸f〇rffl〇terol,茶齡等枝氣管舒張藥，如磷 酸可待因，noscapine，碟酸 dineBorfan， dextromethorphan等鎮咳藥，如奎寧定，毛地黃毒甘， 鹽酸丙芬酮，普羅卡因醯胺等抗心律不整藥，如胺苯甲 酸乙酯，利度卡因，鹽酸地夫卡因等表面麻醉蕖，如 Phenitoin, ethosuxim, ide, prinidon等抗顧癇.藥，氣. 化可體松，氫化潑尼松，triancinolone, betamethasone等合成皮質類固醇，如fanotidine,鹽 酸 ranitidine, cimetidine, sucralfate, sulpride, teprenone,_ plaunotol等消化器用藥，如 indeloxazine· ,idebenone,鹽酸 tiapride,鹽酸 bife丨e 1 ane , hopanten鈣等中樞神經用藥，如pravastatin納等高脂 血症治療藥，如鹽酸安比西林酞，cefotetan, josamycin等抗生素等。 這些藥物中尤具代表性者為鹽酸尼卡地平。又亦可為 生物學半衰期短之藥物。 _物之董只要能呈藥效之量則皆可，但通常為製劑全 體之85重量％以下，尤宜80重量％以下。 為使這些藥物在水分少之結腸也容易吸收，宜使其溶 解性良好。至於改善溶解性之方法（可溶化處理），可 舉出適用於水膠體之公知方法，例如加界面活性劑（聚 氣乙烯硬化蓖麻油類，聚氣乙烯花楸釀高脂肪酸酯類， (請先間讀背面之注意事項再塥寫本頁) -裝- 訂· 缚. 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 __B6_ 五、發明説明（5 ) 聚氣乙烯聚氣丙二醇類，蔗糖脂肪酸酯類等），形成藥 物與助溶劑，如高分子羥丙基甲基纖維素（HPMC),聚乙 烯基吡咯啶酮（PVP)，聚乙二醇（PEG)等水溶性高分子， 羧甲基乙基纖維素（CMEC),羥丙基甲基纖維素酞酸酯 (HPMCP),甲基丙烯酸甲酯-甲基丙烯酸共聚物（商品名 Eudragit L.S. Rohm & Haas公司製造）等腸溶性高分 子）之固體分散體之方法。若藥物為鹼性物質時，也可 加如檸檬酸，酒石酸等有機酸，必要時也可採用作成可 溶性鹽之方法，用環糊精等形成包接化合物之方法。可 溶化之手段可依目的藥物而適宜地變更β 〔内海勇等： 「最近之製劑技術及其應用I」，永井恆司等：醫藥雜 誌157-159 (1983)及「藥學專題論文」號，生物學利用 能，軟體科學社78-82(1988)。 其中宜採用形成藥物與助溶劑之固體分散體來改善溶 解性之方法（日本特開昭56-49314號，FR246Q667號） 0 至於使水浸入之本發明製劑之錠劑内部所用添加劑（ 以下簡稱親水性基劑），此親水性基劑1克溶解所需之 水量在20±5°c為5ml以下，宜4ml以下者，水溶性越高 ，使水浸入錠劑中之效果越高。這種親水性基劑可舉出 如聚乙二醇（PEG,例如商品名PEG 400, 1500，4000, 6000及20000,日本油脂公司製造），聚乙烯基吡咯啶 酮（PVP,如商品名PVP K30, BASF公司製造）等親水性 -7- <請先閲讀、背面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局R工消費合作社印製 A6 B6 五、發明説明（6 ) 高之高分子，如D -花楸醇，木糖醇等糖醇類，如白糖， 無水麥芽糖，D -果糖，聚葡糖（如聚葡耱40)，葡萄糖 等糖類，如聚氣乙烯硬化蓖麻油（HC0,如Cremophor, RH40, BASF公司製造，HC0-40, HC0-60,日光化學公司 製造），聚氣乙烯聚氣丙二醇（如Pluronic F68,旭電 化公司製造等），或聚氣乙烯花揪醏高脂肪酸酯 (Tween,如Tween 80關東化學公司製造）等界面活性 劑，及如氣化納，氣化鎂等鹽，或如檸稼酸，酒石酸等 有機酸，如甘胺酸，/S-丙胺酸，镅酸離胺酸等胺基酸 ，如葡甲胺等胺基糖類。尤宜PEG 6000, PVP，D -花楸 糖醇等。 此親水性基劑之配比乃隨藥物之特性（溶解性，治療 效果等）及其含量，親水性基劑之溶解性，形成水膠體 之高分子之特性，或投予時病人之狀態等種種因子而異 ，惟宜製劑滯留在消化管上部之間完全凝顧化之比率β 製劑滞留在消化管上部之時間乃種類而異，又有個體差 ，狗為投予後約2小時，人為投予後約4〜5小時[B r . J. Clin· Pharmac. (1988)， 26， 435-443]。若為人時 ,宜為投予後4〜5小時能大致完全凝膠化之程度之配比 β —般而言，對製劑全體為5〜80重量％，宜5〜60重量 %。 親水性基劑之含量若過少，則凝膠化不及内部而在結 腸之放出不充分；反之，若含量過多，則雖能在短時間 -8 - (請先閱讀背面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 _B6_ 五、發明説明（7 ) 進行凝膠化，但凝膠易崩解，藥物之溶出提早，有不能 逹成充分徐放化之虞，又因基劑之量也增多，故有製劑 本身大型化等缺點。 作為形成水膠體之高分子物質，須本發明製劑以幾乎 完全凝膠化之狀態耐伴随食物消化之消化管之收縮蓮動 ，保持某程度形狀下往消化管下部之結腸移行，具有凝 膠化時之粘度等之性狀。 適用於本發明製劑之形成水膠體之高分子物質宜為凝 膠化時之粘度高者。尤宜例如1 水溶液（2 5 °C )之拈度 1 0 0 0 c p s以上者。 高分子物質之性狀取決於其分子量，可適用於本發明 製劑之形成水膠體之高分子物質宜更高分子量者，平均 分子量200萬以上，尤宜400萬以上者。 這種高分子物質有例如分子量200萬以上之聚乙烯氣 化物（ΡΕ0),如商品名Polyox WSR-303,平均分子量700 萬，粘度7 5 0 0 - 1 0 0 0 0 c p s ( 1 %水溶液2 5 °C，以下同此測 定），Polyox lfSR Coagulant,平均分子量 500萬，粘 度 5500〜7500cps, Polyox WSR-301，平均分子量 400萬 ,粘度 1 6 5 0 - 5 5 0 0 cps，Polyox WSR-N-60K ,平均分子量 200萬，粘度2000-4000cps(23：水溶液25°C)，以上均 為聯合磺化公司製造；羥丙基甲基纖維素（HPMC),如商 品名 Metolose 90SH100000,粘度 4100-5600cps ( 1% 水 溶液 20°C) , Metolose 90SH50000,粘度 2900-3900cps (請先閲讀f而之注意事項再塡寫本頁) 丨裝· -π Μ. 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6_五、發明説明（8 ) (同上測定），Metolose 90SH30000,粘度25000-3 5 0 0 0 c p s ( 2 %水溶液2 0 °C )，以上均為倍越化學公司製 造；羧甲基纖維素納（CMC-Na)，如商品名為Sunlose F-150MC,平均分子量20萬，粘度1 2 0 0 - 1 8 0 0cps(l%水 溶液25°C) ，Sunlose F-1000MC，平均分子量42萬，拈 度 8000-12000cps (同上測定），Sunlose F-300MC,平 均分子量3 0萬，粘度2 5 0 0 - 3 0 0 0 c p s (同上測定），以上 均為日本製紙公司製造；羥乙基纖維素（HEC),如商品 名HEC Daicel SE 8 5 0 ,平均分子量148萬，粘度2 4 0 0 -3000cps(13：水溶液 2‘5°C) ，HEC Daicel SE900,平均 分子量156萬，粘度4 0 0 0 - 5 0 0 0 cps (同上測定），以上 均為Daicel化學工業公司製造；或羧乙烯基聚合物，如 Carbpol 940，平均分子量約 250 萬，B.F. Goodrich Chemical公司製造等。 宜為平均分子量200萬以上之ΡΕ0ο若須如12小時以上 長期間之持缠放出時，宜更高分子，宜平均分子量400 萬以上，或更高粘度，宜1¾水溶液25 °C之粘度為3000 cps以上之高分子。 這些形成水膠體之高分子物質可用一種或混合二種以 上。由二種以上高分子物質而成且有全體適合本發明性 狀之混合物也適用為形成本發明水膠體之高分子物質。 在人為使具有在結腸之藥物放出性能，須投予後至少 經6〜8小時，尤宜12小時以上時凝膠化製劑之一部分殘 -1 0 - (請先閲讀背面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公鳘） 經濟部中央標準局員工消費合作社印製 A6 B6 五、發明説明（9 ) 存於結腸。 欲作成具有如此性狀之水膠體製劑，雖依製劑之大小 ，高分子物質之種類，藥物及為使水浸入錠劑中之添加 劑之性質及含量等而異，但一般在一錠6G()fflg以下之製 劑時，對製劑金體形成水膠體之高分子物質之配比為10 〜95,宜15〜90重量％毎錠中含有70® g以上，宜loom g 以上。若少於此量，則不能耐長期間在消化管内受浸蝕 ,可能無法達成充分徐放化。 於上述本發明製劑之親水性基劑，形成水膠體之高分 子物質（以下簡稱水膠體形成基劑）之種類及配合量經 由下列實驗確認其有用性。 實驗例 (關於親水性基劑及水膠體形成基劑之種類及配合量〉 ⑴本發明水膠體徐放性製劑之經時凝膠形成速度試料 對水膠體形成基劑Polyox WSR-303 (以下稱Polyox 303) 100重量份配合150重量份親水性基劑PEG6QGG,而 在乳缽中混合，用油壓機以打錠壓1噸/杵打錠，得直 徑8·0醐，每錠20Gmg之錠劑β 凝膠形成試驗 試驗液採用第12版日本藥典崩壊試驗法第2液，依日 本藥典溶出試驗法第2法（奬法）以奬回轉速度25γρβι 進行試驗。定時取出錠劑，剝離凝顧層後，測定無凝膠 化部分之直徑（D obs)e由D obs算出凝膠化率（G)(表 -1 1 - ——----------------,!1------裝--------、玎------線 (請先閲沾？背而之注意事項再塡寫本頁) 本紙張又度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6 五、發明説明（10) 1，圖1，數式1 )。 在此，凝膠化率乃示錠劑中形成凝膠部分之比率。其 算法雖無待定惟可如下將錠劑潤濕一定時間後，测定未 凝膠化部分之體積（或重量），而從試驗前之錠劑之體 積（或重置）減去來求出。 具體而言，將潤濕一定時間之錠劑之凝膠層剝離，測 定未凝膠化部分之直徑（或厚度）而依式1算出。也可 從後述式2求出。 又可利用凝膠層與未形成凝膠部分之強度差，將施加 一定壓力時之直徑（或厚度）為未凝膠化部分之直徑（ 或厚度），而從式1算出。 表1 凝膠形成試驗結果 試驗時間（h) D 〇 b s ( mm ) G (ϋί) 8 . 0 ± 0 . 0 6 · 8 土 0.03 5 . 8 ± 0 . 2 4 · 0 土 0.05 2 · 0 ± 0 · 0 0 3 7·9 土 0.7 6 1 · 1 ± 1 · 8 87 . 9 士 0.4 98.4 ± 0·0 10 0 10 0 ------------------rl·-------裝------#------绮 (請先閲讀背而之注意事項再場寫本頁) (n=3,平均土 s.e) -12- 本紙張A度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 經^F部中央標準局員工消費合作社印製 A6 B6_ 五、發明説明（11) 數式1 (Dobs)3 凝膠化率（G, !K) = (1- -) X 100 (d ini ) 3 D obs:試驗開始後，水未到達部分之直徑 D i n i ·.試驗開始前製劑之直徑 試驗結果 作為親水性基劑，含有PEG 6000之水膠體錠乃以大致 一定速度使内徑縮小而進行凝膠化。在試驗開始2小時 ，水膠體形成基劑大致完全（80%以上）凝膠化。 ⑵有獮親水性基劑之含量 試料 對100重量份水膠體形成基劑Poly ox 303配合0〜150 重量份以下之親水性基劑PEG6000，而在乳缽中混合， 用油壓機以打錠壓1噸/杵打錠，得直徑8 . G ram每錠2 0 0 mg之錠劑。 凝膠形成試驗 試驗液採用第12販日本藥典崩壊試驗法第2液，依日 本藥典溶出試驗法第2法（獎法）以奬回轉速度25γρβ 進行試驗。定時取出錠劑，剝離凝膠層後，測定無凝膠 化部分之直徑（D obs)。由D obs算出凝膠化率（G)(表 2 ，圖 2 ) 〇 -----------------2·"------裝------.玎------線-- (請先閱讀背面之注意事項再塡寫本頁) -13- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 _ B6_ 五、發明説明（12) 表2 凝膠形成試驗結果 處方比 G (% ) POLYOX 303: PEG 6000 - 2 h 4 h 10 0: 0 10 0: 5 1 η ο： ίο 100: 15 100: 25 100: 50 100:100 100:150 29.7±2.9 50.5±1.4 44.2±5.2 7 8.0 ± 2.1 52.3±2.5 83.9±0.5 84.6±0.5 91.2±2.0 8 4 . 6 ± 0.6 N.T. 8 5 . 2 ± 0 . 6 N.T. 87.1+ 0.2 N.T. 87.9±0.4 100.0±0.0 -----------------1-------装------，1τ------緣 一 (請先閲讀背面之注意事項再填寫本頁) Ν.Τ·;未試 （η = 3，平均土 s . e ) 均試驗結果 由於配合15重量份（錠劑重量之13.0%)親水性基劑 PEG6000，在2小時呈現80%以上凝膠化。又由於配合重 量10份（錠劑重量之9.1%)親水性基劑PEG60Q0,在4 小時呈現8 0 %以上凝膠化。 ⑶親水性基劑之篩選 -1 4 - 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 _B6_ 五、發明説明（13) 試料 對10 Q重量份水膠體形成基劑Polyox 3Q3配合1Q0重量 份各種親水性基劑，而在乳缽中混合，用油壓機以打錠 壓1噸/杵打錠，得直徑8·〇™毎錠200mg之錠劑。 凝膠形成試驗 試驗液採用第12販日本藥典崩壤試驗法第2液，依日 本藥典溶出試驗法第2法（獎法）以奬回轉速度25rpm 進行試驗。試驗開始2小時後取出錠劑，知離凝膠層後 ，測定無凝膠化部分之直徑（D obs)e由0 obs算出凝膠 化率（G)(表3,圖3)。 ----------------I-------裝------、玎-------蝝 (請先閱讀背面之注意事項再填寫本頁) -15- 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） A6 B6 五、發明説明（14)表3 各種添加劑之溶解性對凝膠化率之影蜜 添加劑 溶 解 性 G (能溶解 1克之水量） (% ) 無添加 2 9 . 7 土 2 . 9 乳糖 < 8 8t 1 24 · 4 土 1.9 D-甘露醇 < 6 ffl 1 26 . 8士 1 . 9 肌醇 " 4 2 · 0 土 1 . 5 甘胺酸 < 4 ID 1 80 · 9 士 0.7 PEG20000 " 86 . 2 土 0 . 3 Pluronic F 6 8 * ” 9 5 · 1 士 0 . 4 PVP K 3 0 < 2 ml 82 · 2 士 2.5 Dextran40 85 . 9 土 1 . 0 Meglumine U 93 . 4 ± 0.8 無水葡萄耱 ” 94 . 2 土 1.5 離胺酸-HC 1 " 9 5 . 1 土 1.3 /?-丙胺酸 Μ 9 9 · 3 土 0.2 PEG6000 ·< 1 ml 87 . 1 士 0.2 檸橡酸 " 93 · 2 土 0.3 無水麥芽糖 " 93 . 7 土 0.7 木糖醇 Η 94 . 0 ± 1 . 4 蔗糖 Μ 94 . 2 ± 1 . 1 D -花楸醇 ” 97 · 0 ± 0.4 D-果糖 ri- 100 *聚氣乙烯[160 ]聚氧丙烯[30 ]二醇 （n = 3 ,平均± S . E .) (請先閲讀背面之注意事項再填寫本頁) 丨裝. 、11. 丨線· 經濟部中央標準局員工消費合作社印製 註：溶解1克所箱之水量（20 土 5 ^ )，依日本藥.典通 則溶解性之測定方法。 -16- 本紙張又度適用中國國家標準（CNS)甲4规格（210 X 297 ;釐） 經濟部中央標準局員工消費合作社印製 A6 _ B6_ 五、發明説明（is) 試驗結果 添加具有溶1克添加劑需水6或8 m 1之溶解性之D -甘 露醇及乳糖時，呈現與單獨Polyox 303時大致相等凝腠 化率，表示凝膠化至錠劑内部之效果低。 得知為使2小時之凝膠化8 0 %以上之親水性基劑宜為 甘胺酸，PVP K30, PEG6000, D -花揪醇等溶解性高之基 劑（至少溶解1克添加劑所需水量為5nl以下，宜4ml以 下）。 ⑷水膠體形成基劑之檢討 以乙醯胺芬.（acetoaminophen)及鹽酸尼卡地平（Pd)為 模型藥物，檢討作為徐放性製劑所需之水膠體形成基劑 配合量及分子量。 其1 適宜配合量之檢討 調査凝膠形成基劑之配合量與溶出舉動之關偽 ①乙酿胺芬（acetoaminophen) 表4 ---------------------：——裝------、玎-------線 < · (請先閲讀背面之注意事項再塡寫本頁) 處方 （ffl g ) 乙m胺芬 50 5 0 50 50 5 0 PEG6000 5 0 50 50 5 0 50 POLYOX303 40 50 10 0 15 0 300 重量 （mg) 14 0 150 200 250 4 0 0 直徑 （mm) 6.5 7.0 8 . 0 8 . 5 9 . 5 -17- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 處方（mg) 噴乾品 1 128 128 128 128 128 128 128 PE66000 32 32 32 32 32 32 32 POLY0X303 64 96 120 160 200 240 320 重量（mg) 2 2 4 2 5 6 2 8 0 3 2 0 3 6 0 4 0 0 4 6 0 直徑（mm) 8.5 8.5 8.5 9.0 9.0 9.5 10.0 A6 B6_ 五、發明説明（16) 將表4之成分在乳缽中混合後，用油壓機以打錠壓1 噸/杵打錠，得錠劑（含50mg乙醯胺芬）。 ②鹽酸尼卡地平（Pd) 將1重量份Pd，0.2重量份HC0-6D, 0.4重量份羥丙基 甲基纖維素（TC-5E,信越化學公司製造）溶在水-甲醇 混液（1: 9),而以噴乾機來噴蓀乾燥，作為噴乾品1 β 表5 將表5之成分在乳缽中混合，而用油壓機以打錠壓1 噸/杵打錠，得錠劑（含80mg Pd)。 溶出試驗 試驗液採用曰本藥典崩壊試驗法第1液或第2液而依 曰本藥典溶出試驗法第2法（奬法），就乙醯胺芬及鹽 酸尼卡地平（Pd)之模型製劑進行試驗，定時取樣而依UV 法測定溶液中之藥劑量（圖4，圖5 ) β -1 8 - 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） ------------------------裝------訂-------練！ (請先閲讀背面之注意事項再塡寫本頁) 經濟部中央標準局員工消費合作社印製 經濟部中央標準局員工消費合作社印製 A6 ____B6_ 五、發明説明（17) 試驗結果 得知可由水膠體形成基劑Polyox 303之含量控制溶出 速度β若以乙醯胺芬50fflg為主藥時，可配合Polyox 303 含量lOOmg (錠劑重量之503!>以上，則在高攪拌下（奬 轉速200rpn, pH 6.8)也能持缠放出12小時以上。同樣 ，以Pd 8〇Bg為主藥時，配合Polyox 3 03含量96|^(錠 劑重量之37 .5%)以上，則在高撗拌下（獎_速2 ΟΟγρβ ，Ρ Η 1 . 2 )也能持缠放出1 2小時以上。 水膠體形成基剤之適宜含有率乃視藥劑及親水性基劑 之種類及量，及所求溶出速度等而異，惟含有率越大則 放出越慢β又若欲持缅放出12小時以上時，宜每錠含水 膠體形成基劑約7〇Bg以上，尤宜lOQmg以上。 其2 凝膠形成基劑之分子童與放出持鑛時間之關傜之 檢討 ①乙醛胺芬 表6 (請先閲讀“背面之注意事項再填寫本頁) 丨裝_ d. 處方 重量份 乙醒胺芬 50 P E G 6 0 0 0 5 0 聚乙烯氧化物（PE0) 250 聚乙烯氣化物（PE0)採用平均分子量90萬，100萬， -1 9- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 _B6_ 五、發明説明（18 ) (請先閱讀背面之注意事項再填寫本頁) 200萬，400萬，500萬或700萬者。在乳缽中混合後，用 油壓機以打錠壓1噸/杵打錠，得直徑9.Dim,毎錠350 mg# 〇 ⑵鹽酸尼卡地平（P d ) 將1重量份Pd, 0.4重量份HCO-40, (K8重量份羥丙基 甲基纖維素（TC-5E,信越化公司製造）溶在水-甲醇1 :9混液後，用噴乾機來噴霧乾燥，而當作噴乾品2 表7 錠劑處方 重量份 噴乾品2 178 PEG6000 48 聚乙烯氣化物（ΡΕ0) 344 至於聚乙烯氣化物（ΡΕ0)採用分子量90萬，100萬， 200萬，400萬，500萬或700萬者。在乳缽中混合後，用 油壓機以打錠壓1噸/杵打錠，得直徑11.0關，每錠 568mg錠劑（含 80mg Pd)。 溶出試驗 經濟部中央標準局员工消費合作社印製 仿前其1就適宜配合量檢討所作溶出試驗，處理乙_ 胺芬處方製劑及鹽酸尼卡地平處方製劑（圖6，圖7) -20- 本紙張尺J变適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（l9) 試驗結果 得知隨水膠體形成基劑聚乙烯氧化物（PEO)之平均分 子量而溶出速度起變化。若以乙醯胺芬5 0 mg為主藥時， 經濟部中央標準局員工消費合作社印製 子量4 0 0 拌下（奬轉速2Q0rpB, pH 6. 上。 同樣，若以Pd 80iag為主藥 2 0 0萬以上级，刖可持缠放d ⑸在活體内凝膠形成之確認 試料 對水膠髏形成基劑（Polyo 6000，PVP K30, D -花楸醇） 缽中混合後，用油壓機以打 8.0ηπ,每錠2fl0rag之錠劑。 P0LY0X303:PEG6000= 100:1 P0LY0 X 3 0 3 :PVP K 3 0 = 1 0 0 :1 POLY0X303:D-花楸醇=100: 狗解剖試驗 對絶食約2 0小時之雄小獵 製劑及水3 Q m 1 , 2小時後， 脱血及開腹。從消化管回收 出凝膠化率（G)，如表8。 然在高摄 8)也能持绩放出12小時以 時，用ΡΕ0之平均分子量 1 2小時以上。 X 303)將親水性基劑（PEG 按下列配比添加者各在乳 錠壓 1噸 /杵 打錠 ,得直徑 0 , 2 5 , 5 〇 , 1 0 0 0 , 2 5 , 1 00 10 , 2 5, 10 0 犬（ 狗A, B) 經口 投予各種 以戊 基巴 比妥 納麻 醉而予以 錠劑 而潮 定D 〇 b s , 由此算 (請先閱讀背面之注意事項央填寫本頁) -2 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6B6 五、發明説明（20)表8 狗解剖試驗結果 狗 投與試 驗 回收 解 剖 試驗 結果 活體外 (P0LY0X303 10 0:) 位置 D 〇 b s (mm) 6 (%) G (%) A PEG6000 10 結腸 6 . 8 38.6 52.3 PEG6000 2 5 結腸 2 . 8 95.7 84.6 P E G 6 0 0 0 50 結腸 無 檢 出 10 0 85.2 PEG6000 100 結腸 無 檢 出 10 0 87.1 PVP K30 1 0 0 結腸 無 撿 出 10 0 8 2.2 D-花揪醇 10 0 結腸 無 檢 出 10 0 97.0 B PEG6000 10 胃 3 . 2 9 3.6 5 2.3 PEG6000 2 5 胃 2 . 9 95.2 84.6 PVP K30 10 胃 2 . 5 96.9 - PVP K30 25 胃 2 . 9 9 5.2 - D-花楸醇 10 胃 2 . 3 97.6 - D -花楸醇 2 5 胃 2 . 9 9 5.2 - ——---------------------装------，玎-------蟓 (請先閲讀背&之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 試驗結果 狗A在投予後2小時，錠劑已移至結腸，錠劑在消化 管上部滯留時間為2小時以下。但配合1 0份P E G 6 0 0 0之 -22 木紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 _ B6_ 五、發明説明（21) 錠劑以外，均凝膠化8 G %以上，與活體外之結果大致相 田 〇 狗B在投予後2小時，錠劑仍滯留在胃内，所有錠劑 均凝膠化8 0 %以上。 從以上結果得知，將能在活體外凝膠化80 %以上之親 水性基劑（PVP K30, PEG6000, D-花楸醇）適量配合之 水膠體錠劑在活體内也使水浸入錠劑内部而易凝膠化。 本發明製劑必要時可加其他藥學容許之添加劑，如賦 形劑，粘合劑，崩壞劑，滑澤劑，芳番劑，着色劑，保 存劑，肋溶劑，界面活性劑等。 本發明製劑為具有水膠體形成能力之一定形狀之固型 製劑，其製法任何能適用於通常水膠體製劑之方法均可 。例如形成藥物，親水性基劑，及形成水膠體之高分子 物質，必要時可混合其他添加劑，而依壓縮成形之打辞· 法，膠囊壓縮充填法，或將混合物熔解後，固化成形而 擠壓成形法。又可在成形後，予以一般糖衣，膜衣等加 衣處理，或成形後充填在膠囊。 ---.--------------I------裝------.玎------練 (請先閲讀背面之注意事項再塡寫本頁) 法，錠 在該 方質打 ·可當 之物接 ，兼 劑子直 時可 製分之 理也 體高錠 處劑 膠之打 溶基 水體及 肋性 般膠合 以水 一水混 予親 於成以 物之 用形予 藥明 適及而 之發 能劑， 劑本 有基劑 製。 法性加 明行 製水添 發施 之親他 本前 劑，其 於之 製物加 用化 明藥時 適劑 發如要 將製 本例必 C欲逑 ，又法 上 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 五、發明説明（22: A6 B6 溶劑 助加 來添 劑需 加所 添他 他其 其及 需， 所質 及物 劑子 基分 C 性高造 水之製 親體來 由膠法 將水方 如成之 例形錠 ，及打 劑物來 溶藥入 助之加 .1 速 部覆 放被 速劑 有製 而明 要發 需本 應於 可如 也例 劑 ， 製U 性ar 放P 徐se. 之ea pn 1 ffl, 6 發r 本te οα ， ·1 外ed。 此mm部 U放 後含 間物 時藥 定加 一 增 求如 要例 若 ί 如快 例度 〇 遵 劑出 錠溶 核物 有藥 成以 作， 而時 的度 目濃 依中 可血 又高 更 量 藥 筝少基 量減性 含 { 水 劑度親 ,*•1―SN, 性速少 水出減 親溶或 加物 \ 增藥及 或遲量 \延含 及則劑 ，分基 劑部成 基層形 成外體 形，膠 體錠水 膠核加 水作增 少當量 減方含 ，處物 度 出 溶 物 藥 之 後 間 時 定. 一 S 加 可 也明 .説 )單 等簡 量之 含面 劑圖 有 含 0 示果 乃結 1 驗 圖試 成 形 膠 凝 之 劑 製 性 放 徐 體 膠 水 之 (請先閱讀背面之注意事項再填驚本頁) .裝， 訂. 將 示 乃 2 圖 結 驗 試 成 形 膠 凝 之 時 化 變 量 含 之 果 結 之 率 化 膠 凝 之 後 時 小 2 之 劑 基 性 水 親 種 各 示 乃 3 圖 <yM. 果 經濟部中央標準局員工消費合作社印製 1/ } ο ο ο 平 ly丨ly地 ο ο P 芬 P 卡 示胺示尼 乃醯乃酸 4乙 5 鹽 圖為圖為 物 物 藥 傜 關 之 動 舉 出 容 與 量 合 配 之 藥 /(\ 偽 關 之 non 舉 出 容 與 量 合 配 之 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6_ 五、發明説明（23) 圖6乃示PEO分子量與溶出舉動之關傜（藥物為乙醯 胺芬> 。 圖7乃示PEO分子量與溶出舉動之關傜（藥物為鹽酸 尼卡地平）。 圖8乃示實施例1及比較處方1之依奬法之溶出試驗 結果β 圖9乃示實施例1及比較處方1之凝膠試驗結果。 圖10乃示實施例1及比較處方1之狗血漿中藥物濃度 。推移之結果。 圖11乃示比較處方1之溶出試驗結果及依解迴旋 (Deconvolution)法之_吸收舉動。 圖12乃示實施例1之溶出試驗結果及依解迴旋法之吸 收舉動。 圖13乃示實施例2及比較處方2之狗血漿中藥物濃度 推移。 圖14乃示實施例3 (SR)及比較處方3 (SR)之依漿法之 溶出試驗結果。 圖15乃示實施例3及比較處方3之狗血漿中藥物濃度 推移。 圖16乃示實施例4及5之依漿法之溶出試驗結果。 圖17乃示實施例6 , 7及10之依$法之溶出試驗結果 f \ 圖18乃示實施例12及比較處方4之依學法之溶出試驗 -25- ——_--------------I------裝------，玎------線 (請先閲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)甲4規格（2]0 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6 五、發明説明（24) 結果。 圖19乃示實施例12及比較處方4之狗血漿中藥物濃度 推移。 實施發明之最佳形態 玆詳逑本發明製劑，但本發明不並限於這些實施例〇 實施例1 AAP 100重量份 PEG6000 400 Polyox303 300 將乙醯胺芬（AAP)及PEG6000在80°C熔融後，冷卻固化 而粉碎之。粉碎物與P〇lyox 3 0 3在乳缽中混合後，用油 膣機以打錠壓1噸/杵打錠，得直徑9咖，每錠40Qmg( 含5〇Bg AAP)之錠劑。 比較處方1 AAP 1 0 0重量份 Polyox303 200 將AAP及Polyox303在乳缽混合後，用油壓機以打錠壓 1噸/杵打錠，得直徑8.5和!8,每錠30〇1^(含1〇〇通8 AAP)之錠劑。 就以上所得賁施例1及比較處方1進行如下試驗。 ⑴溶出試驗 試驗液採用日本藥典崩壞試驗法第2液，依日本藥典 溶出試驗法第2法（獎法）進行試驗。定時取樣而依UV -2 6 - ----'----------------------裝------，玎-------^ (請先閲讀背而之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 _B6_ 五、發明説明（25) 法測定溶液中之AAP (表9 ,圖8 )。 表9Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A6 _B6_ V. Description of the Invention (1) Technical Field The present invention relates to a radioactive preparation that can release drugs for a long period of time. The colon at the lower part of the tube is also a hydrocolloid release agent that allows the drug to be released well. BACKGROUND ART Conventionally, various kinds of hydrocolloid preparations have been proposed in order to make medicines gradually released. For example, Japanese Unexamined Patent Publication No. 62-120315 proposes to shape and compress a drug with a water-soluble polymer capable of forming a hydrocolloid and an enteric coating base. Japanese Unexamined Patent Publication No. 63-215620 proposes to A core made of a high-molecular polymer substance and a hydrocolloid preparation made of a water-soluble polymer substance as a base. Japanese Patent Publication No. 40-2053 states that drugs and gasified ethylene polymers are added with hydrophilicity if necessary. Entangled preparations made of sexual substances. However, these drugs are intended to be held in the upper part of the digestive tract, such as the small intestine, to release the drug, and are not intended to release the drug to the lower part of the digestive tract, such as the colon. It is a release agent that releases and absorbs drugs while descending inside the digestive tract. Its drug absorption and release in the upper part of the digestive tract has a great influence on bioavailability, but it is less affected by moisture and aging contents in the colon. The effects of drug release were previously considered to be difficult to release, but no research was conducted on drug release (the 6th Annual Conference of the Pharmaceutical Society lecture on the Winter Collection (Heisei 2)), 30 pages, Pharia. Tech. Japan 8 (1), (1 9 9 2), 4 1 pages > 0 Although the biological half-life of the drug itself is also for review of radioactive preparations -3-(Please read the notes on the back before quoting this page) This paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of the invention (2) (Please read the precautions on the back before writing this page), but for the drug itself For drugs with short half-lives, Xian believes that it is difficult to fully release them (Monthly Journal of Pharmaceutical Affairs 25 (1 1), (19 8 3), page 29). The invention shows that the inventors are studying the release of drugs, It is found that if it stays in the stomach and small intestine on the upper part of the digestive tract, it will absorb water into the medicine When the drug is migrated to the lower part of the digestive tract in an almost completely gelled state, the drug can be released in the colon with little water, and the present invention is finally completed. That is, the present invention is a hydrocolloid release agent, including at least one or more drugs Additives that immerse water into the tablets, and ⑶ polymer materials that form hydrocolloids, have the ability to retain gelation in the stomach and small intestine in the upper part of the digestive tract, and release the drug in the colon in the lower part of the digestive tract. In the present invention, the state where the preparation is almost completely gelled means that about 70% of the preparation, preferably more than about 80%, is in a state of gelation. The release agent of the present invention can also be regarded as absorbed by the colon. The absorption time of the drug is greatly prolonged, so it can be stabilized in the blood concentration of the drug. That is, the preparation of the present invention is almost completely gelled because it absorbs water in the upper part of the digestive tract, while eroding the surface of the preparation, it goes to the digestive tract. The lower part migrates and is more eroded and releases the drug, so it can achieve good and persistent drug absorption in the colon with little water. Central Bureau of Standards, Ministry of Economic Affairs The consumer-friendly cooperative prints the Xufang preparation of the present invention in more detail as follows. One or more medicines suitable for the lozenges of the present invention are not limited as long as the medicine for the purpose of Xufanghua is acceptable. -4-This Paper size applies to China National Standard (CNS) A4 (210 X 297 mm). Printed by A6 B6 of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (3) The representative drug can be indomethacin, Diazepine, Digassin Sodium, Codeine, Ibuprofen, Phentermine, Oxyphenbutasone, Mepirizole, Aspartame, Ethenzamide, acetoaminophen, Antipyrine, Finacetin, Bromobutyl Scopolamine , Morphine, etonidoline, pentazocin, senoprofen and other anti-inflammatory, antipyretic or analgesic drugs, such as isoniazid, ethanbutol hydrochloride, and other anti-tuberculosis drugs, such as isosorbide nitrate, nitroglycerin, nifedipine, bannidipine hydrochloride, and nicardipine hydrochloride , Dipyridamol, anrinone, strong acid indenol, strong acid hydralazine, methyldopa, furosemide, spirono]. Acton, quanethidine nitrate, Lixepin, araosulalol and other circulators , Such as gastroprozine hydrochloride, amitriptylin hydrochloride, neinonapride, haloperidol, moperone, perphenazine, — HY (diazepam), lorazepam, chlorcliazepoxide and other antipsychotic drugs, maleic acid felamine, strong acid diphenhydramine and other anti-tissue drugs , Such as thiamine nitrate, tocopherol acetate, Cyc 〇tiamine, P yridoxa 1, cobamide, ascorbic acid, nicotinamide and other vitamin drugs, such as allopurinol, colchicine, probenecid and other gout drugs, such as isoprene Hypnotic hypnotic drugs such as bital, valprofen, midazolam, argonaldehyde, etc., such as fluorouracil, cariaofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa and other anti-malignant tumor drugs, such as phenylpropanolamine, ephedrine and other anti-stasis Blood medicine, diazepam, insulin, tolbutamide and other diabetic drugs, such as hydrothiazide, -5- (Please read the precautions on the back first and write this page)-Pack. Applicable standards_China A Standard (CNS) A4 specification (210 X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A6 __ _B6_ (4) Polythiazide, triamteren and other diuretics, such as aninophylline, fumaric acid, and bronchodilators such as tea age, such as codeine phosphate, noscapine, DineBorfan, dextromethorphan and other antitussives, such as Quinine, digoxigenin, profenone hydrochloride, procaine, and other antiarrhythmic drugs, such as ethylaminobenzoate, lidocaine, and difcaine hydrochloride, and other anesthetics such as Phenitoin, ethosuxim, ide, prinidon and other anti-epileptic drugs. Drugs, gas. Cortisol, prednisone, triancinolone, betamethasone and other synthetic corticosteroids, such as fanotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpride, teprenone, plaunotol, etc. Organ medications, such as indeloxazine ·, idebenone, tiapride hydrochloride, bife 丨 e 1 ane, hopanten calcium and other central nerve medications, such as pravastatin and other hyperlipidemia treatment drugs, such as ampicillin hydrochloride, cefotetan, josamycin and other antibiotics. The most representative of these drugs is nicardipine hydrochloride. It can also be a short biological half-life drug. As long as it can exhibit a medicinal effect, it is usually not more than 85% by weight, and more preferably 80% by weight or less. In order to make these drugs easy to absorb in the colon with little water, it is better to make them soluble. As for the method for improving the solubility (solubilization treatment), there are known methods applicable to hydrocolloids, such as adding a surfactant (polygas ethylene-cured castor oil, polygas ethylene calyx to brew high fatty acid esters, (please Read the precautions on the back first, and then transcribe this page)-binding-binding · binding. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A6 __B6_ V. Description of the invention (5) Polyethylene, polyethylene, propylene glycols, sucrose fatty acid esters, etc.), forming drugs and co-solvents, such as high molecular hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), water-soluble polymers such as polyethylene glycol (PEG), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl cellulose phthalate (HPMCP), methyl methacrylate-methyl A method for solid dispersion of an acrylic copolymer (enteric polymer such as Eudragit LS Rohm & Haas). If the drug is a basic substance, organic acids such as citric acid and tartaric acid can also be added. If necessary, a method of forming a soluble salt and a method of forming an inclusion compound by using cyclodextrin or the like can also be adopted. Means of solubilization can be changed as appropriate depending on the target drug [Utsui Yu et al .: "Recent Formulation Technology and Application I", Nagai Hiroshi et al .: Medical Journal 157-159 (1983) and "Pharmaceutical Monograph", Bioenergy Utilization, Software Science Society 78-82 (1988). Among them, a method for improving the solubility by forming a solid dispersion of a drug and a co-solvent is recommended (Japanese Patent Application Laid-Open No. 56-49314, FR246Q667). 0 As for the additives used in the tablet of the present invention (hereinafter referred to as hydrophilic) Base), the amount of water needed to dissolve 1 gram of this hydrophilic base is 5ml or less, preferably 4ml or less, the higher the water solubility, the higher the effect of water immersion in the lozenge. Examples of such a hydrophilic base include polyethylene glycol (PEG, for example, trade names PEG 400, 1500, 4000, 6000, and 20000, manufactured by Nippon Oil & Fats Co., Ltd.), and polyvinylpyrrolidone (PVP, such as trade name PVP). K30, manufactured by BASF) and other hydrophilic -7- < Please read the notes on the reverse side before copying this page) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) Printed by A Ronghua Consumer Cooperative of Central Standards Bureau of Ministry of Economic Affairs A6 B6 5 6. Description of the invention (6) High polymers, such as sugar alcohols such as D-anisol and xylitol, such as white sugar, anhydrous maltose, D-fructose, polyglucose (such as polyglucose 40), glucose and other sugars , Such as polyethylene gas hardened castor oil (HC0, such as Cremophor, RH40, manufactured by BASF, HC0-40, HC0-60, manufactured by Nikko Chemical Co., Ltd.), polyethylene gas, polypropylene glycol (such as Pluronic F68, manufactured by Asahi Denka, etc.) ), Or surfactants such as polyethylene gas calyx high fatty acid esters (Tween, such as Tween 80 manufactured by Kanto Chemical Co., Ltd.), and salts such as sodium gasification, magnesium gasification, or organics such as citric acid, tartaric acid, etc. Acids, such as glycine, / S-alanine, osmic acid, and other amino acids, such as meglumine and other amino sugars. Especially suitable are PEG 6000, PVP, D-Sorbusol. The ratio of this hydrophilic base is based on the characteristics of the drug (solubility, therapeutic effect, etc.) and its content, the solubility of the hydrophilic base, the characteristics of the polymer that forms the hydrocolloid, or the state of the patient at the time of administration, etc. Various factors vary, but it is advisable that the ratio of the drug staying in the upper part of the digestive tract to be fully coagulated. Β The time for the drug to stay in the upper part of the digestive tract varies according to the type, and there are individual differences. The dog is about 2 hours after administration. About 4 to 5 hours after the administration [B r. J. Clin. Pharmac. (1988), 26, 435-443]. In the case of humans, it is preferable that the formulation ratio β is such that it can be substantially completely gelled 4 to 5 hours after administration. Generally, it is 5 to 80% by weight, and preferably 5 to 60% by weight for the entire preparation. If the content of the hydrophilic base is too small, the gelation will not be as good as the inside and the release in the colon will not be sufficient; on the other hand, if the content is too large, it can be released in a short time -8-(Please read the precautions on the back before copying Page) This paper size is in accordance with China National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A6 _B6_ V. Description of the invention (7) Gelation, but the gel is easy Disintegration, early dissolution of the drug, there is a risk that it cannot be fully released, and because the amount of the base agent is also increased, there are disadvantages such as the large size of the preparation itself. As a polymer that forms a hydrocolloid, the preparation of the present invention must be resistant to contraction of the digestive tract accompanied by food digestion in a state of almost complete gelation, and maintain a certain shape and migrate to the colon at the lower part of the digestive tract with gelation. Properties such as viscosity at the time. The hydrocolloid-forming polymer substance suitable for the preparation of the present invention is preferably one having a high viscosity when gelled. Particularly preferred is, for example, an aqueous solution (2 5 ° C) with a degree of latitude above 1 0 0 0 c p s. The properties of the polymer substance depend on its molecular weight, and the hydrocolloid-forming polymer substance suitable for the preparation of the present invention is preferably one with a higher molecular weight, an average molecular weight of more than 2 million, and particularly preferably more than 4 million. Such high molecular substances are, for example, polyethylene vapors (PE0) with a molecular weight of more than 2 million, such as the trade name Polyox WSR-303, an average molecular weight of 7 million, and a viscosity of 7 500-1 0 0 0 0 cps (1% aqueous solution 2 5 ° C, same measurement below), Polyox lfSR Coagulant, average molecular weight 5 million, viscosity 5500-7500 cps, Polyox WSR-301, average molecular weight 4 million, viscosity 1 6 5 0-5 5 0 0 cps, Polyox WSR-N -60K, average molecular weight 2 million, viscosity 2000-4000cps (23: aqueous solution 25 ° C), all of which are manufactured by United Sulfonation; hydroxypropyl methylcellulose (HPMC), such as trade name Metaloose 90SH100000, viscosity 4100- 5600cps (1% aqueous solution at 20 ° C), Metolose 90SH50000, viscosity 2900-3900cps (please read the precautions of f before writing this page) 丨 installed · -π Μ. This paper standard applies to China National Standard (CNS) A 4 Specifications (210 X 297 mm) A6 B6 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (8) (same as above), Metaloose 90SH30000, viscosity 25000-3 5 0 0 0 cps (2% aqueous solution 20 ° C), all of which are manufactured by Beyond Chemicals; Sodium cellulose (CMC-Na), such as the trade name Sunlose F-150MC, with an average molecular weight of 200,000 and a viscosity of 12 0 0-1 0 0 cps (l% aqueous solution 25 ° C), Sunlose F-1000MC, with an average molecular weight 420,000, degree 800-12000 cps (determined as above), Sunlose F-300MC, average molecular weight 300,000, viscosity 2 500-3 0 0 cps (determined as above), all of which are manufactured by Japan Paper Co .; hydroxyethyl Cellulose (HEC), such as the trade name HEC Daicel SE 8 50, with an average molecular weight of 1.48 million and a viscosity of 24 0 0-3000 cps (13: aqueous solution 2'5 ° C), HEC Daicel SE900, with an average molecular weight of 1.56 million and viscosity 4 0 0 0-5 0 0 cps (determined as above), all of which are manufactured by Daicel Chemical Industries; or carboxyvinyl polymers, such as Carbpol 940, with an average molecular weight of about 2.5 million, manufactured by BF Goodrich Chemical. It should be PE0 with an average molecular weight of 2 million or more. If it needs to be released for a long period of time of more than 12 hours, it should be higher molecular weight, preferably with an average molecular weight of 4 million or higher viscosity, or 1¾ aqueous solution at 25 ° C. The viscosity is 3000. Polymers above cps. These hydrocolloid-forming polymer materials may be used singly or in combination of two or more kinds. Mixtures composed of two or more kinds of high-molecular substances and having all properties suitable for the present invention are also suitable as high-molecular substances forming the hydrocolloid of the present invention. A part of the gelled preparation is artificially left at least 6 to 8 hours after the administration of the drug in the colon, and preferably more than 12 hours. -1 0-(Please read the notes on the back before copying Page) This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 gong). Printed by A6 B6, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (9) It is stored in the colon. To make a hydrocolloid preparation with such characteristics, although it depends on the size of the preparation, the type of polymer substance, the nature and content of the drug and the additives used to immerse the water in the lozenge, etc., it is generally 6G () fflg in one tablet For the following preparations, the ratio of the polymer material that forms the hydrocolloid to the gold body of the preparation is 10 to 95, preferably 15 to 90% by weight. The osmium tablet contains more than 70 g, and preferably more than loom g. If it is less than this amount, it will not be able to withstand erosion in the digestive tract for a long period of time, and it may not be able to achieve sufficient radiochemical release. In the above-mentioned hydrophilic base of the preparation of the present invention, the type and compounding amount of the hydrocolloid-forming polymer substance (hereinafter referred to as the hydrocolloid-forming base) and its blending amount were confirmed by the following experiments. Experimental Example (Types and blending amounts of hydrophilic bases and hydrocolloid-forming bases) 之 The time-dependent gel formation speed test sample of the hydrocolloid-releasing formulation of the present invention is based on Polyox WSR-303 (hereinafter referred to as hydrocolloid-forming base) Polyox 303) 100 parts by weight with 150 parts by weight of a hydrophilic base PEG6QGG, mixed in a mortar, and pressed with a hydraulic press at a rate of 1 ton per pestle to beat ingots to obtain a tablet diameter of 8 · 0 醐, 20Gmg per tablet. Β The gel formation test test liquid is the second liquid of the 12th edition of the Japanese Pharmacopoeia disintegration test method, and the test is performed according to the second method of the Japanese Pharmacopoeia dissolution test method (reward method) at a prize rotation speed of 25γρβι. The tablets are taken out regularly, and the gel layer is peeled ， Measure the diameter (D obs) of the gel-free part and calculate the gelation rate (G) from Dob (Table-1 1---------------------, ! 1 ------ install --------, 玎 ------ line (please read the dip first? Be careful not to write this page again) This paper is suitable for China Standard (CNS) A4 specification (210 X 297 mm) A6 B6 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (10) 1, Figure 1, Equation 1) Here, the gelation rate Noshi The ratio of the gel portion in the lozenge. Although the algorithm is not yet determined, the volume (or weight) of the ungelatinized portion can be measured after wetting the lozenge for a certain time, and the volume of the lozenge before the test ( Or reset). Specifically, the gel layer of the tablet wetting for a certain period of time is peeled off, and the diameter (or thickness) of the non-gelatinized portion is measured and calculated according to Equation 1. It can also be described later It can be calculated by Equation 2. The difference in strength between the gel layer and the non-gelatinized portion can be calculated from Equation 1 by using the diameter (or thickness) of a non-gelatinized portion when a certain pressure is applied. Table 1 Results of gel formation test Test time (h) D 〇bs (mm) G (ϋί) 8 0 ± 0. 0 6 · 8 soil 0.03 5. 8 ± 0. 2 4 · 0 soil 0.05 2 · 0 ± 0 · 0 0 3 7 · 9 soil 0.7 6 1 · 1 ± 1 · 8 87. 9 ± 0.4 98.4 ± 0 · 0 10 0 10 0 ----------------- -rl · ------- install ------ # ------ qi (please read the precautions before writing this page) (n = 3, average soil se)- 12- The A degree of this paper is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Printed by A6, B6_, Consumer Cooperatives of the Central Bureau of Standards F. Fifth, the description of the invention (11) Formula 1 (Dobs) 3 Gelation rate (G,! K) = (1--) X 100 (d ini) 3 D obs: After the test, the diameter D ini of the part that did not reach the water. The diameter test result of the preparation before the test was started. As a hydrophilic base, the hydrocolloid tablet containing PEG 6000 reduced the inner diameter at a certain rate to gel. Into. At 2 hours from the start of the test, the hydrocolloid-forming base gelled almost completely (more than 80%). The content of the hydrophilic base agent is mixed with 100 parts by weight of the hydrocolloid-forming base Poly ox 303, and the hydrophilic base agent PEG6000 of 0 to 150 parts by weight is mixed in a mortar. Tons per pestle to obtain tablets with a diameter of 8.20 ram per tablet. Gel formation test The test liquid was the second liquid of the Japanese Pharmacopoeia Collapse Test Method No. 12 and the Japanese Pharmacopoeia Dissolution Test Method No. 2 (Prize Method) was used to perform the test at a prize rotation speed of 25γρβ. The tablets were taken out at regular intervals, and after peeling off the gel layer, the diameter (D obs) of the non-gelatinized portion was measured. Calculate the gelation rate (G) from Dobs (Table 2, Figure 2) 〇 ----------------- 2 · " -------- install-- ---. 玎 ------ line-- (Please read the notes on the back before writing this page) -13- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ) Printed by A6 _ B6_ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (12) Table 2 Gel formation test result prescription ratio G (%) POLYOX 303: PEG 6000-2 h 4 h 10 0: 0 10 0 : 5 1 η ο: ίο 100: 15 100: 25 100: 50 100: 100 100: 150 29.7 ± 2.9 50.5 ± 1.4 44.2 ± 5.2 7 8.0 ± 2.1 52.3 ± 2.5 83.9 ± 0.5 84.6 ± 0.5 91.2 ± 2.0 8 4. 6 ± 0.6 NT 8 5. 2 ± 0. 6 NT 87.1+ 0.2 NT 87.9 ± 0.4 100.0 ± 0.0 ----------------- 1 ------- install- -----, 1τ ------ Yuan Yi (Please read the notes on the back before filling this page) Ν.Τ ·; not tested (η = 3, average soil s. E) All test results are due to 15 parts by weight (13.0% of the weight of the tablet) of the hydrophilic base PEG6000 was blended, and gelled at 80% or more in 2 hours. In addition, due to the addition of 10 parts by weight (9.1% of the tablet weight) of the hydrophilic base PEG60Q0, more than 80% gelation occurred in 4 hours. ⑶ Screening of hydrophilic bases-1 4-This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A6 _B6_ V. Description of the invention (13) The sample was mixed with 10 Q parts by weight of hydrocolloid-forming base Polyox 3Q3 and 1 Q0 parts by weight of various hydrophilic bases, mixed in a mortar, and pressed with a hydraulic press at a rate of 1 ton / punch to obtain a diameter of 8 · 〇 ™. 200mg tablets. Gel formation test The test liquid was the second liquid of the twelfth Japanese Pharmacopoeia collapse test method, and the second pharmacopoeia dissolution test method second method (reward method) was used to perform the test at a prize rotation speed of 25 rpm. The tablet was taken out 2 hours after the start of the test, and after the gel layer was known, the diameter (D obs) of the non-gelated portion was measured and the gelation rate (G) was calculated from 0 obs (Table 3, Figure 3). ---------------- I ------- install ------, 玎 ------- 蝝 (Please read the precautions on the back before (Fill in this page) -15- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of invention (14) Table 3 Effect of solubility of various additives on gelation rate Honey Additive Solubility G (Ability to dissolve 1 gram of water) (%) No addition 2 9.7 Soil 2.9 Lactose < 8 8t 1 24 · 4 soil 1.9 D-mannitol < 6 ffl 1 26. 8 ± 1. 9 inositol " 4 2 · 0 soil 1.5 glycine < 4 ID 1 80 · 9 person 0.7 PEG20000 " 86. 2 soil 0. 3 Pluronic F 6 8 * ”9 5 · 1 person 0.4. 4 PVP K 3 0 < 2 ml 82 · 2 ± 2.5 Dextran 40 85. 9 soil 1.0 Meglumine U 93. 4 ± 0.8 anhydrous grape vine "94. 2 soil 1.5 lysine-HC 1 " 9 5. 1 soil 1.3 /?- Alanine M 9 9 · 3 soil 0.2 PEG6000 · < 1 ml 87 .1 ± 0.2 Citrus Auronic Acid " 93 · 2 Soil 0.3 Anhydrous Maltose " 93. 7 Soil 0.7 XylitolΗ 94.0 0 ± 1.4 Sucrose M 94.2 2 ± 1.1 D- Anthocyanin "97 · 0 ± 0.4 D-fructose ri- 100 * Polyethylene ethylene [160] polyoxypropylene [30] glycol (n = 3, average ± S. E.) (Please read the precautions on the back first (Fill in this page again) 丨 Package. 、 11. 丨 Line printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Note: Dissolve 1 gram of water in the box (20 soil 5 ^), according to the Japanese medicine. Method -16- This paper is again applicable to China National Standard (CNS) A4 specifications (210 X 297; centimeters) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A6 _ B6_ V. Description of the invention (is) Test results are added with When dissolving 1 gram of the additive requires 6 or 8 m 1 of soluble D-mannitol and lactose, the gelation rate is approximately the same as that of Polyox 303 alone, indicating that the effect of gelling into the interior of the lozenge is low. In order to make the gelation of 80% or more in 2 hours, the hydrophilic base is preferably glycine, PVP K30, PEG6000, D-anthopol, etc. Highly decomposable base (the amount of water needed to dissolve at least 1 gram of the additive is less than 5nl, preferably less than 4ml). 检讨 The review of hydrocolloid formation base is based on acetoaminophen and nicardipine hydrochloride (Pd). Model drugs, review the amount and molecular weight of hydrocolloid-forming bases required for Xuanfang preparations. Part 1 Review of suitable blending amounts Investigate the relationship between the amount of gel-forming bases and the dissolution behavior ① Ethylamine ( acetoaminophen) Table 4 ---------------------: —— install -------- 、 玎 ------- line < (Please read the notes on the back before copying this page) Prescription (ffl g) Ethylamine 50 5 0 50 50 5 0 PEG6000 5 0 50 50 5 0 50 POLYOX303 40 50 10 0 15 0 300 Weight (Mg) 14 0 150 200 250 4 0 0 Diameter (mm) 6.5 7.0 8. 0 8. 5 9. 5 -17- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) prescription (Mg) Spray dried product 1 128 128 128 128 128 128 128 PE66000 32 32 32 32 32 32 32 POLY0X303 64 96 120 160 200 240 320 Weight (mg) 2 2 4 2 5 6 2 8 0 3 2 0 3 6 0 4 0 0 4 6 0 Diameter (mm) 8.5 8.5 8.5 9.0 9.0 9.5 10.0 A6 B6_ V. Description of the invention (16) After mixing the ingredients in Table 4 in a mortar, use an oil press to press 1 ton per pestle to beat the ingot. Obtained lozenges (containing 50mg acetaminophen). ② Nicardipine hydrochloride (Pd) 1 part by weight of Pd, 0.2 parts by weight of HC0-6D, 0.4 parts by weight of hydroxypropylmethyl cellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) are dissolved in a water-methanol mixture (1: 9), and spray-dried with a spray dryer, as the spray-dried product 1 β Table 5 The ingredients in Table 5 were mixed in a mortar, and an oil press was used to press the tablet with a ton of 1 ton per pestle to obtain a tablet ( Contains 80mg Pd). The dissolution test test solution uses the first or second liquid of the Pharmacopoeia disintegration test method, and the model preparation of acetaminophen and nicardipine hydrochloride (Pd) according to the second method (award method) of the dissolution test method of the Pharmacopoeia. Carry out tests, take regular samples and measure the dose of the drug in the solution according to the UV method (Figure 4, Figure 5) β -1 8-This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) --- --------------------- Install ------ Order ------- Practice! (Please read the notes on the back before writing this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed by A6 ____B6_ V. Description of the invention (17) The test results show that the hydrocolloid The content of the base forming agent Polyox 303 is used to control the dissolution rate β. If acetaminophen 50fflg is used as the main drug, the content of Polyox 303 can be 100mg (503 of tablet weight! ≫ above, under high agitation (reward speed 200rpn, (pH 6.8) can also be released for more than 12 hours. Similarly, when Pd 80Bg is used as the main medicine, the content of Polyox 3 03 is 96 | ^ (37.5% of the weight of the tablet), and it is mixed under high pressure. (Award_speed 2 〇Ογρβ, P Η 1.2) can also be released for more than 12 hours. The appropriate content of hydrocolloid formation base depends on the type and amount of the agent and the hydrophilic base, and the required dissolution rate It varies, but the larger the content rate, the slower the release of β, and if it is released for more than 12 hours, it is preferable that the hydrocolloid forming base of each tablet is about 70Bg or more, and more preferably 10Qmg or more. 2 Gel-forming base Review of the relationship between the molecular child of the agent and the release of the holding time ① Aldehyde Fen Form 6 (Please read the “Precautions on the back before filling in this page”) 丨 Packing _ d. Prescribed weight parts of Acetaminophen 50 PEG 6 0 0 0 5 0 Polyethylene oxide (PE0) 250 Poly Ethylene vapor (PE0) uses an average molecular weight of 900,000, 1 million, -1 9- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) A6 _B6_ V. Description of the invention (18) (Please Read the notes on the back before filling in this page) 2 million, 4 million, 5 million or 7 million. After mixing in a mortar, use an oil press to beat ingots with a ton of 1 ton / pestle to get the diameter 9.Dim,毎 Tablet 350 mg # 〇⑵ Nicardipine hydrochloride (P d) 1 part by weight of Pd, 0.4 parts by weight of HCO-40, (K8 parts by weight of hydroxypropyl methyl cellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) After the water-methanol 1: 9 mixture, spray-dry with a spray dryer and use it as a spray-dry product 2 Table 7 Lozenge prescription weight parts spray-dry product 2 178 PEG6000 48 Polyethylene vapor (PEE) 344 As for polyethylene The gaseous substance (PE0) is one with a molecular weight of 900,000, 1 million, 2 million, 4 million, 5 million, or 7 million. After mixing in a mortar, use an oil hydraulic machine to press the tablet 1 / Punch the tablets to get a diameter of 11.0, each tablet is 568mg tablets (containing 80mg Pd). Dissolution test Dissolution test before the imitation of the first batch of the review of the appropriate blending amount before processing by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, dissolving ethylamine Fen prescription and Nicardipine hydrochloride prescription (Figure 6, Figure 7) -20- This paper rule J becomes applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of the invention (l9 The test results show that the dissolution rate varies with the average molecular weight of the hydrocolloid-forming base polyethylene oxide (PEO). If 50 mg of acetaminophen is used as the main medicine, the sub-quantity printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs will be printed at 4 0 0 (reward speed 2Q0rpB, pH 6. Same. If Pd 80iag is used as the main medicine Above 200,000, 刖 can hold the d ⑸ 凝胶 in the living body to confirm the formation of the gel sample hydrogel cross base (Polyo 6000, PVP K30, D-anthocyanin) mixed in a bowl, using an oil press Take 8.0ηπ, 2fl0rag tablets per tablet. P0LY0X303: PEG6000 = 100: 1 P0LY0 X 3 0 3: PVP K 3 0 = 1 0 0: 1 POLY0X303: D-Anthocyanin = 100: Anatomical test of dogs on hunger strike About 20 hours of male poaching preparation and 3 Q m 1 of water. After 2 hours, the blood was dehydrated and the abdomen was opened. The gelation rate (G) was recovered from the digestive tract, as shown in Table 8. However, it can also be maintained at high photo 8) For 12 hours or more, the average molecular weight of PE0 is 12 hours or more. X 303) The hydrophilic base agent (PEG is added in the following proportions, and each of them is pressed at a ton of 1 ton per cup to obtain a diameter of 0, 25, 5 0, 1 0 0, 2 5, 1 00 10, 2 5, 10 0 Dogs (dogs A and B) were orally administered with various pentyl barbituran anesthesia and given tablets in order to determine D 〇bs, which is calculated (please read the notes on the back first to complete this Page) -2 This paper size is in accordance with China National Standard (CNS) A4 specification (210 X 297 mm) A6B6 V. Description of invention (20) Table 8 Dog dissection test results Dog administration test Recovery dissection test results in vitro (P0LY0X303 10 0 :) Position D 〇bs (mm) 6 (%) G (%) A PEG6000 10 Colon 6. 8 38.6 52.3 PEG6000 2 5 Colon 2. 8 95.7 84.6 PEG 6 0 0 0 50 No colon detected 10 0 85.2 PEG6000 100 No colon detected 10 0 87.1 PVP K30 1 0 0 No colon detected 10 0 8 2.2 D-Analcohol 10 0 No colon detected 10 0 97.0 B PEG6000 10 Stomach 3. 2 9 3.6 5 2.3 PEG6000 2 5 Stomach 2. 9 95.2 84.6 PVP K30 10 Stomach 2. 5 96.9-PVP K30 25 Stomach 2. 9 9 5.2-D-Anthocyanin 10 Stomach 2. 3 97.6-D-Anthocyanin 2 5 Stomach 2. 9 9 5.2-------------------------- Packing ------,玎 ------- 蟓 (Please read the notes on the back & then fill out this page) The test results printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy Dog A 2 hours after the administration, the tablets have been moved to the colon The retention time of the tablet in the upper part of the digestive tract is less than 2 hours. However, with 10 parts of PEG 6 0 0 of -22, the paper size of the paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Central of the Ministry of Economy Printed by the Consumer Bureau of Standards Bureau A6 _ B6_ V. Description of the invention (21) Except for the tablets, all gelled above 8 G%, which is roughly the same as the results in vitro. Dog B remained in the tablets 2 hours after administration In the stomach, all lozenges gelled more than 80%. From the above results, it is known that a hydrocolloid lozenge (PVP K30, PEG6000, D-Anthocyanin), which can gel more than 80% of gel in vitro, can also be immersed in the lozenge in vivo. Internal and easy to gel. The preparation of the present invention may be supplemented with other pharmaceutically acceptable additives, such as excipients, binders, disintegrating agents, lubricating agents, aromatic agents, coloring agents, preservatives, rib solvents, surfactants, etc., if necessary. The preparation of the present invention is a solid preparation of a certain shape having hydrocolloid forming ability, and the preparation method can be any method that can be applied to the usual hydrocolloid preparation. For example, to form drugs, hydrophilic bases, and macromolecules that form hydrocolloids, if necessary, other additives can be mixed, and according to the compression molding method, capsule compression filling method, or the mixture is melted, solidified, and squeezed. Press forming method. After forming, it can be coated with ordinary sugar coating, film coating, etc., or filled into capsules after forming. ---.---------- I ------ install ------. 玎 ------ exercise (please read the precautions on the back first) (Written on this page) method, the ingot is connected to the square material and can be connected to the material, and the agent can be divided into pieces. The principle of the ingot preparation is to dissolve the base water and the ribs and glue it with water. Water is mixed with the energizing agent which is suitable for use in the form of medicine, and the agent has a base. Addition of pro-drugs and pro-drugs for the production of water by the law of Jiamingxing, the preparation of which is added with chemical medicines, and the appropriate agent should be used if the system is to be used. Standard (CNS) A4 specification (210 X 297 mm) V. Description of the invention (22: A6 B6 Solvent-assisted additives need to be added to other and more needs, quality and physical properties of the sub-components C The parent body of high water production is an example of injecting the water side into a tablet by the gel method, and the dissolving agent is added to help the medicine. 1 The speed part is covered by the speed agent, and it should be issued if necessary. Another example is the preparation of U, ar, P, and Se. Ea pn 1 ffl, 6 hairs r this te ο α, · 1 outside ed. This mm part of U after the addition of interstitial drugs must be increased by one as required. If ί is as fast as the standard, the nucleus nucleus produced by the tablet is medicated, and the concentration of the current concentration is high, the blood is high, the amount is low, and the amount is reduced. It contains {water agent degree, * • 1 ―SN, slow speed, low water release, reduced affinity or additions, drug addition and / or delay, and extension of the regular agent, the base agent part forms a base layer to form an outer body shape, colloidal tablet water Adding water to the nucleus to increase or decrease the equivalent weight, the formula is included, and the amount of the solution is determined after the solution is dissolved. One S plus can also be clear. Say) A simple and simple amount of the facial preparation chart contains 0, which indicates that the result is 1 The figure shows the gelation agent. It is made by putting the body glue (please read the precautions on the back before filling this page). Install, order. Include the time-varying variables of the figure 2 when testing and forming the gel. The rate of the fruit set is gelled after gelling, and the water-based parent species are shown in Figure 3. < yM. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 1 /} ο ο ο Pingly 丨 ly ο ο P fen P Calamine linolenic acid 4 ethyl 5 salt The picture shows the object The movement of Yaotongguan includes medicines with combined volume and volume / (\ The pseudo of Guanguan non lists the papers with combined capacity and quantity. The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Economy Printed by A6 B6_, Consumer Cooperatives of the Central Bureau of Standards of the People's Republic of China. 5. Description of the invention (23) Figure 6 shows the relationship between PEO molecular weight and dissolution behavior (drug is acetaminophen). Figure 7 shows PEO molecular weight and dissolution behavior. Guan Qin (medicine is nicardipine hydrochloride). Figure 8 shows the results of the dissolution test according to the prize method in Example 1 and Comparative Formula 1 β Figure 9 shows the results of the gel test in Example 1 and Comparative Formula 1. Figure 10 Shows the drug concentration in dog plasma of Example 1 and Comparative Prescription 1. The results are shown in Figure 11. Figure 11 shows the dissolution test results of Comparative Formula 1 and the absorption behavior according to the Deconvolution method. Figure 12 shows the Example Dissolution test results of 1 and absorption behavior according to the solution of maneuver Figure 13 shows the change in drug concentration in the plasma of dogs of Example 2 and Comparative Prescription 2. Figure 14 shows the results of the dissolution test according to the pulp method of Example 3 (SR) and Comparative Prescription 3 (SR). Figure 15 shows the implementation Example 3 and comparison of drug concentration in dog plasma in comparison prescription 3. Figure 16 shows the results of the dissolution test according to the pulp method of Examples 4 and 5. Figure 17 shows the dissolution tests according to the $ method according to Examples 6, 7 and 10. Results f \ Fig. 18 shows the dissolution test according to the method of Example 12 and Comparative Prescription 4 -25- ---------------- I ------ pack- -----, 玎 ------ line (please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 specification (2) 0 X 297 mm) Economy Printed by A6, B6, Consumer Cooperatives of the Ministry of Standards and Standards of the People's Republic of China 5. The Invention (24) Results. Figure 19 shows the change in drug concentration in the blood plasma of dogs in Example 12 and Comparative Prescription 4. The best form of implementing the invention is detailed in the present invention. Preparation, but the present invention is not limited to these examples. Example 1 AAP 100 parts by weight of PEG6000 400 Polyox303 300 Melting acetaminophen (AAP) and PEG6000 at 80 ° C, cooling The pulverized material was mixed with Pollyox 303 in a mortar, and then pressed with an oil maker with a ton of 1 ton / pestle to obtain a 9-gauge diameter, each 40Qmg (containing 50Bg AAP). ) Tablets. Comparative prescription 1 AAP 100 parts by weight Polyox303 200 After mixing AAP and Polyox303 in a mortar, use an oil hydraulic machine to press the tablet with a ton of 1 ton / pest to obtain tablets with diameters of 8.5 and 1.8, each tablet at 30%. 1 ^ (containing 100 Tong 8 AAP) tablets. The following tests were performed with respect to the obtained Example 1 and Comparative Formula 1. ⑴ Dissolution test The test solution is the second liquid of the Japanese Pharmacopoeia disintegration test method, and the test is performed according to the second method (the award method) of the Japanese pharmacopoeia dissolution test method. Sampling at regular intervals and according to UV -2 6-----'---------------------- installation ------, 玎 ----- -^ (Please read the precautions on the back before transcripting this page) The paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 _B6_ V. Description of the invention (25) Method for measuring solution AAP (Table 9, Figure 8). Table 9

活體外溶出試驗結果（％)(日藥典2液、獎法200rpnO 時間（h) 0.0 0.5 1.0 2.0 3.0 4.0 6.0 8.0 10.0 12.0 比較處方 1 0·0 9.4 15.7 25.8 34.7 42.8 56.5 68.3 78.4 86.4 實施例 1 0.0 8.8 1 3.2 2 1.8 _32.4 3 9 . 1 55.3 69.2 8 1 . 9 92 .1 ⑵凝膠形成試驗 試驗液採用日本藥典崩壞試驗法第2液，依日本藥典 溶出試驗法第2法（槳法）以奬轉速2 5 r pm進行試驗。 •定時取出錠劑，測定未凝膠化部分及凝膠層之直徑（D obs)，由此算出凝膠化率（G)，如表10,圖9。 ----'---------------------裝---------，玎-------繪 (請先間讀背面之注意事項再塡寫本頁) 經濟部中央標準局員工消費合作社印製 -27- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（26) 表10 凝膠形成試驗結果 試驗時.間 Dobs G 製 劑 （h) (mu) (% ) (請先閱讀背面之注意事項再填寫本頁) 比較處方1 0 8.5 - 2 7.8±0.2 21·5±7·6 4 7.5±0·1 30·0±2.5 6 6·7±0·1 50·4±3.0 —裝. 實施例1 0 9.0 - 2 5.6±0.03 76.2±0.3 4 3.1±0.01 96·0±0.1 6 0 ±0.00 100.0±0 · 經濟部中央標準局員工消費合作社印製 (η = 3，平均土 s . e .) ⑶狗投予試驗 對絶食約2 0小時之雄小獵犬（η = 4 )將實施例1之錠劑 X2錠（AAP lOOmg)及比較處方 1 (AAP lOOmg)與水 30ml 一起經口投予。經時採血而依HPLC/UV法測定血漿中藥 物濃度（表1 1，圔1 0 ) β吸收速度則以A A P 1 0 0 b g水溶 液靜眤投予時之血漿中藥物濃度數據為加權傜數而依解 -28- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 五、發明説明（27) 迴旋法算出。以實施例之錠劑投予後2 4小時之吸收率為 100 (見表 12)。 表1 1 藥動力學參數 製劑 AUC 0 -24 C max T max MRT (ng · h/»l) (ng/ml) (h) (h) 比較處方1 1469.7 ± 537.5 343.7± 21 · 7 1.3± 0.3 4.0土 1.2 實施例1 2702·8士 151.5 349 _ 9± 36 · 1 1 · 5± 0.3 7 . 0土 0.3 (n = 4，平均土 s · e ·) 表12 錠劑 對狗 經口投與 時之吸 收率 (% ) 時間 (h) 0 . 0 0 . 5 1.0 2 . 0 3 . 0 4.0 6 . 0 比較 處方 1 0 . 0 8.1 1 8.7 2 7.2 3 3.3 3 7 . 8 45.9 實施 例1 0.0 7.5 1 4 . 3 3 1.0 3 9.1 4 5 . 9 60.2 -2 9- 本紙張又度適用中國國家標準（CNS)甲4規格（210 X 297公釐） -·請先閱讀背而之注意事項再填寫本頁) 五、發明説明（28) 時間（h ) 8 . 0 1 0 . 0 1 2 . 0 2 4 .0 比較處方 1 50.3 5 3.1 5 5.4 58.8 實施例 1 75.5 87.4 95.6 100.0 (請先閲讀背面之注意事項年塡寫本頁) 經濟部中央標準局員工消費合作社印製 試驗結果 在活體外溶出試驗，比較處方1與實施例1呈現大致 同樣之溶出舉動（圖8,表9),但水之浸入速度（凝 膠化率）大不相同（圖9，表10)。這些製劑對狗經口 投予之結果，與比較處方1投予時相較，實施例1投予 時之血漿中藥物濃度推移顯然為持缠性（圖10) 。S比 較處方1投予時之血漿中藥物濃度時間曲線下面積（AUC) 及平均體内滞留時間（MRT)之參差甚大，此可推定為基 於消化管移動時間之値體差（表11) β反觀實施例1投 予時之A U C及M R Τ則個體差小，暗示難受消化管移動速度 之影饗。又因吸收時間會持绩，故實施例1投予時之最 高血漿中藥物濃度（Cmax)與比較處方1投予時者大致相 等，但A ϋ C則增大約1 . 8倍。 比較由解迴旋之吸收舉動及溶出試驗結果。在比較處 第1投予，製劑滞留於消化管上部之約2小時呈現與活 體外溶出結果一樣之吸收，但2小時以後則顯著地抑制 吸收（圖1 1，表1 2 ) ^在狗絶食條件下，消化管上部滯 -3 0 - 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公澄） 經濟部中央標準局員工消費合作社印製 A6 B6_ 五、發明説明（29) 留時間為約2小時，得知在消化管下部藥物難溶出及吸 收。反觀實施例1投予時，呈現與活體外溶出試驗之結 果大致相同之吸收β即與消化管上部一樣，製劑在消化 管下部也顯示藥物溶出及吸收均佳（圖12，表12)。 ⑷狗解剖試驗 用絶食約2 0小時之雄小獵犬3隻。解剖之2 , 4及6小 時前，將各種製劑與水3Gml—起經口投予，在戊基巴比 妥鈉之麻醉下解剖而脱血後，開腹而調査製劑之消化管 内之位置（表13)。另小腸部予以5等分，從上部起分 別為小腸1，2，3 , 4 , 5 β k驗結果： 表13 消化管内之位置 狗 Ho. 2 小 時 4小時 6小時 th 較 處方1 1 結 腸 結 腸 結 腸 2 胃 結 腸 結 腸 3 小 腸 5 結 腸 結 腸 實 施 例1 1 結 腸 結 腸 結 腸 2 胃 結 腸 結 腸 3 小 腸 5 結 腸 結 腸 -31- 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） ---：---------------------装------訂-------線 (請先閱讀背面之注意事項再塡寫本頁) A6 B6 五、發明説明（30) 可見藉配合凝膠化率低之比較處方1與親水性基劑而 提高凝膠化率之實施例1在活體内呈大致同樣之消化管 内移動。投予2小時後，兩製劑均有1例滞留在胃，但 其餘存在於小腸5及結腸。故如以往所知，在狗絶食條 件下，製劑之消化管上部之滯留時間為約2小時β即實 施例1投予時，2小時以後所示之髙血中濃度乃與製劑 存在於消化管下部無關，藥物從製劑之溶出良好，確認 起因於充分吸收。 實施例2In vitro dissolution test results (%) (Japanese Pharmacopoeia 2 solutions, 200rpnO time (h) 0.0 0.5 1.0 2.0 3.0 4.0 6.0 8.0 10.0 12.0 Comparative prescription 1 0 · 0 9.4 15.7 25.8 34.7 42.8 56.5 68.3 78.4 86.4 Example 1 0.0 8.8 1 3.2 2 1.8 _32.4 3 9. 1 55.3 69.2 8 1. 9 92.1 The test solution for the gel formation test uses the second liquid of the Japanese Pharmacopoeia disintegration test method, and the second method of the dissolution test method of the Japanese Pharmacopoeia (paddle) Method) The test is performed at a prize speed of 2 5 r pm. • The tablets are taken out at regular intervals, and the diameter (D obs) of the non-gelatinized part and the gel layer is measured to calculate the gelation rate (G), as shown in Table 10, Figure 9. ----'--------------------- install ---------, 玎 ------- draw ( Please read the precautions on the back before writing this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -27- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A6 B6 5 Description of the invention (26) Table 10 Results of gel formation test. Dobs G preparation (h) (mu) (%) (Please read the notes on the back before filling this page) Comparative prescription 1 0 8.5-2 7.8 ± 0.2 21 · 5 ± 7 · 6 4 7.5 ± 0 · 1 3 0 · 0 ± 2.5 6 6 · 7 ± 0 · 1 50 · 4 ± 3.0 —packed. Example 1 0 9.0-2 5.6 ± 0.03 76.2 ± 0.3 4 3.1 ± 0.01 96 · 0 ± 0.1 6 0 ± 0.00 100.0 ± 0 · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (η = 3, average soil s.e.) ⑶ Dog administration test For male beagles (η = 4) on a hunger strike for about 20 hours, the tablet X2 of Example 1 Tablets (AAP 100mg) and Comparative Prescription 1 (AAP 100mg) were orally administered with 30ml of water. Blood was collected over time and the plasma drug concentration was determined by HPLC / UV method (Table 11, 1, 10). AAP 1 0 0 0 bg aqueous solution of the drug concentration data in plasma at the time of static administration is a weighted value and is based on the solution of -28- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) V. Invention Explanation (27) Calculated by the convolution method. The absorption rate of the tablets in the example after 24 hours is 100 (see Table 12). Table 1 1 Pharmacokinetic parameters Formulation AUC 0 -24 C max T max MRT (ng · h / »l) (ng / ml) (h) (h) Comparative prescription 1 1469.7 ± 537.5 343.7 ± 21 · 7 1.3 ± 0.3 4.0 ± 1.2 Example 1 2702 · 8 ± 151.5 349 _ 9 ± 36 · 1 1 · 5 ± 0.3 7. 0 0.3 (n = 4, average soil s · e ·) Table 12 Absorption rate (%) time (h) of tablets when oral administration to dogs 0. 0 0. 5 1.0 2. 0 3. 0 4.0 6. 0 Comparative prescription 1 0. 0 8.1 1 8.7 2 7.2 3 3.3 3 7. 8 45.9 Example 1 0.0 7.5 1 4. 3 3 1.0 3 9.1 4 5. 9 60.2 -2 9- This paper is also applicable to Chinese national standards ( CNS) A4 specifications (210 X 297 mm)-· Please read the precautions before filling out this page) 5. Description of the invention (28) Time (h) 8. 0 1 0. 0 1 2. 0 2 4.0 Comparative Prescriptions 1 50.3 5 3.1 5 5.4 58.8 Example 1 75.5 87.4 95.6 100.0 (Please read the notes on the reverse side of this page for the first year) The results of the printed test results printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in vitro dissolution test Although Comparative Formulation 1 and Example 1 exhibited approximately the same dissolution behavior (Fig. 8, Table 9), the penetration rate (gelation rate) of water was greatly different (Fig. 9, Table 10). As a result of oral administration of these preparations to dogs, the change in drug concentration in plasma at the time of administration in Example 1 was apparently entangled when compared with the administration in Comparative Prescription 1 (Fig. 10). S Comparing the area under the drug concentration time curve (AUC) and the mean in vivo retention time (MRT) of plasma concentration at the time of administration of prescription 1 is very different, which can be presumed to be the carcass difference based on the time of movement of the digestive tract (Table 11) β In contrast, the AUC and MR T at the time of administration in Example 1 are small, which implies that the speed of the digestive tract movement is uncomfortable. Since the absorption time will be sustained, the highest plasma drug concentration (Cmax) at the time of administration in Example 1 is approximately equal to that at the time of administration of Comparative Prescription 1, but A ϋ C increases approximately 1.8 times. The results of the absorption behavior and dissolution test from untwisting are compared. In the first administration of the comparative place, the preparation stayed in the upper part of the digestive tract for about 2 hours and showed the same absorption as the in vitro dissolution result, but after 2 hours, it significantly inhibited the absorption (Figure 11 and Table 1 2) ^ on a fasting dog Under the conditions, the upper part of the digestive tract lags -3 0-This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 Gongcheng) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A6 B6_ V. Description of the invention (29) The retention time was about 2 hours. It was found that the drug was difficult to dissolve and absorb in the lower part of the digestive tract. In contrast, when administered in Example 1, the absorption β, which was approximately the same as the results of the in vitro dissolution test, was the same as that of the upper part of the digestive tract, and the preparation also showed good drug dissolution and absorption in the lower part of the digestive tract (Figure 12, Table 12). Dog walking anatomy test Three male beagle dogs on a hunger strike for about 20 hours. 2, 4 and 6 hours before dissection, various preparations and 3Gml of water were administered orally. After dissection under the anesthesia of sodium pentobarbital and blood removal, the abdomen was opened to investigate the position in the digestive tube of the preparation (Table 13). Another small intestine was divided into 5 equal parts, from the upper part of the small intestine 1, 2, 3, 4, 5 β k test results: Table 13 Position of the digestive tract dog Ho. 2 hours 4 hours 6 hours th than the prescription 1 1 colon Colon 2 Gastric Colon Colon 3 Small Intestine 5 Colon Colon Example 1 1 Colon Colon Colon 2 Gastric Colon Colon 3 Small Intestine 5 Colon Colon -31- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)- -: --------------------- install ------ order ------- line (please read the precautions on the back before 塡(Write this page) A6 B6 V. Explanation of the invention (30) It can be seen that the formula 1 and the hydrophilic base are used to increase the gelation rate by comparing prescription 1 with a low gelation rate, and Example 1 moves in the living body approximately in the same digestive tract. . Two hours after administration, one of the two preparations remained in the stomach, but the rest was present in the small intestine 5 and the colon. Therefore, as is known in the past, the retention time of the upper part of the digestive tract of the preparation is about 2 hours under the condition of fasting of dogs. The lower part is irrelevant, and the drug dissolves well from the preparation, and it is confirmed that the drug is caused by sufficient absorption. Example 2

Pd 1 6 0 (重量份） HC0-60 80 T C- 5 E 16 0 P E G 6 0 0 0 4 0 0 POLYOX303 240 將鹽酸尼卡地平（Pd)，HC0-60，TC-5E及PEG6000溶在 混合溶劑（二氣甲烷/甲醇），用噴乾機來噴霧乾燥。 將噴乾品及P〇ly〇x303在乳缽中混合後，用油壓機以打 錠壓1噸/杵打錠，得直徑9.0m，每錠346.7mg (含Pd 53 . 2mg)之錠劑。 (請先閱讀背面之注意事項再填寫本頁) -裝. 訂 經濟部中央標準局貝工消費合作社印製 -32- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（31) 比較處方2 Pd T w e e η 8 0 CMEC POLY0X303 1 3 Ο (重量份 2 6 13 0 5 7.2 徐放部（SR)Pd 1 6 0 (parts by weight) HC0-60 80 T C- 5 E 16 0 PEG 6 0 0 0 4 0 0 POLYOX303 240 Dissolve nicardipine hydrochloride (Pd), HC0-60, TC-5E and PEG6000 in a mixture The solvent (digas methane / methanol) was spray-dried with a spray dryer. After the spray-dried product and Polly 303 were mixed in a mortar, the tablet was pressed with a hydraulic press at a rate of 1 ton per pestle to obtain a tablet having a diameter of 9.0 m and 346.7 mg (including Pd 53.2 mg) per tablet. (Please read the precautions on the back before filling this page) -Packing. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Bayer Consumer Cooperatives -32- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) A6 B6 V. Description of the invention (31) Comparative prescription 2 Pd T wee η 8 0 CMEC POLY0X303 1 3 〇 (parts by weight 2 6 13 0 5 7.2 Xu Fang Bu (SR)

PdPd

TC-5E 3 0 15 速放部 （QR) 經濟部中央標準局員工消費合作社印製 將鹽酸尼卡地平（Pd), Tween80及CMEC溶在二氣甲烷 及甲醇混液，用噴乾機來噴霧乾燥。將噴乾品與Polyox 3 0 3混合後，用油壓機以打錠壓0 . 8噸/杵打錠，得直徑 8 . 0咖，每錠1 7 1 · 6 m g (含P d 6 5 m g )之錠劑（S R )。另將 Pd及TC-5 E溶在二氣甲烷與甲醇之混液，用塗布機在SR (Pd 65mg)被覆速放部（QR, Pd 15mg)，得每錠 194.1mg 之比較處方 2 (Pd 80mg)。 就以上所得實施例2及比較處方2進行下列試驗β ⑴溶出試驗 試驗液採用日本藥典崩壞試驗法第1液，依日本藥典 溶出試驗法第2法（奬法）以獎轉速2 0 0 r ρ β進行試驗。 定時取樣而依U V法測定溶液中之P d (表1 4 )。 表14 溶出試驗結果 3 3 - 本紙張尺度適用中國國家標準（CNS)甲4規格（2]0 X 297公發） -----^--------------I------裝-------.玎--------^ (請先閱讀背面之注意事項再填寫本頁) 五、發明説明（32) A6 B6 時間（h) 1.0 2.0 3.0 4.0 5.0 6. 0 8.0 10.0 12.0 比較處方 2 1 1.9 29.4 46.4 61.9 74.4 82.1 92.1 97.7 100.0 (SR) 實施例 2 14.0 28.7 45.1 60.5 73 . 1 82.2 94.3 99.8 99.3 (請先閲讀背面之注意事項再塡寫本頁) ⑵凝膠形成試驗 試驗液採用日本藥典崩壊試驗法第1液，依日本藥典 溶出試驗法第2法（獎法）以槳轉速25 rpm進行試驗。 2小時後取出錠劑，測定未凝膠化部分及凝膠層之直徑 (D obs)，由此算出凝膠化率（G),如表15» 表15 凝膠形成試驗結果 丨裝. 製 劑 試驗時間（h) D obs (mm) G (X) 比較處方2 0 8.0 - (SR) 2 無變化 ， 0 經濟部中央標準局員工消費合作社印製 實施例2 0 9 . 0 - 2 5.4±0.02 76.2±0.3 (π = 3，平均士 s · e ) -34- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局員工消費合作杜印製 A6 B6 五、發明説明（33) ⑶狗投予試驗 對絶食約2 0小時之雄小獵犬（η = 6 )將實施例2之錠劑 Χ3錠（Pd 160mg)及比較處方2之錠劑Χ2錠（Pd 160mg) 與水3Qb1—起經口投予。經時採血而依HPLC/UV法測定 血漿中藥物濃度（表16，圖13)。 表16 藥動力學參數 製劑 AUC 0-24 C max T max (ng · h/ml) (ng/ml) (h) 實施例 2 (Pd 160mg) 375.7±89·3 52·9±15.5 7.3±3.5 比較處方 2(Pdl60mg)125.0±31.8 53·6±12.5 1_3±0.2 (n = 6,平均 ±s.e.) 試驗結果 在活體外溶出試驗，比較處方2 (SR)與實施例2呈現 大致同樣之溶出舉動（表14) ，但水之浸入速度（凝膠 化率）大不相同（表15)。這些製劑對狗經口投予之結果 ，與比較處方2投予時相較，實施例2投予時之血漿中 藥物濃度推移顯然為持缠性。另比較處方2投予時，製 劑向消化管下部移行之2小時以後，血漿中藥物濃度顯 本紙張尺度適用中國國家標準（CNS)甲4規格（2]0 X 297公釐） ---.--------------,1------裝------’玎------線 (請先閱讀背面之注意事項再填寫本頁) A6 B6 五、發明説明（34) 著減少，得知在消化管下部藥物難溶出及吸收。反觀實 施例2投予時，在向消化管下部移行之2小時以後，仍 維持血漿中藥物濃度，顯然在消化管下部之藥物溶出及 吸收良好。又因吸收時間會持缠，故實施例2投予時之 最高血漿中藥物濃度（C nax)與比較處方2投予時者大 致相等，但A U C則增大約3 . Q倍。 實施例3 6 δ (重置份） 13 徐放部（SR) 6 5 65 6 5TC-5E 3 0 15 Quick-Release Department (QR) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, dissolving nicardipine hydrochloride (Pd), Tween80 and CMEC in a mixture of methane and methanol, and spray drying with a spray dryer . After mixing the spray-dried product with Polyox 3 0 3, use a hydraulic press to press the tablet with 0.8 ton / penetrate to obtain a tablet with a diameter of 8 0. Each tablet is 17 1 · 6 mg (including P d 6 5 mg) Lozenges (SR). In addition, Pd and TC-5 E were dissolved in a mixture of methane and methanol, and the rapid-release part (QR, Pd 15mg) was covered with an applicator at SR (Pd 65mg) to obtain 194.1mg of each tablet. Comparative prescription 2 (Pd 80mg) ). The following tests were carried out on the Example 2 and Comparative Formula 2 obtained above. Β Dissolution test The test solution was the first liquid of the Japanese Pharmacopoeia disintegration test method, and the second method (the award method) of the Japanese Pharmacopoeia dissolution test method was used at a prize speed of 2 0 0 r ρ β is tested. Samples were taken at regular intervals to determine P d in the solution according to the U V method (Table 14). Table 14 Dissolution test results 3 3-This paper size applies to China National Standard (CNS) A4 specifications (2) 0 X 297 public hair) ----- ^ -------------- I ------ install -------. 玎 -------- ^ (Please read the notes on the back before filling this page) V. Description of the invention (32) A6 B6 Time ( h) 1.0 2.0 3.0 4.0 5.0 6. 0 8.0 10.0 12.0 Comparative prescription 2 1 1.9 29.4 46.4 61.9 74.4 82.1 92.1 97.7 100.0 (SR) Example 2 14.0 28.7 45.1 60.5 73. 1 82.2 94.3 99.8 99.3 (Please read the note on the back first (Notes on this page) (1) The gel formation test test solution uses the first liquid of the Japanese Pharmacopoeia disintegration test method, and the test is performed according to the second method (award method) of the Japanese Pharmacopoeia dissolution test method at a paddle speed of 25 rpm. After 2 hours, the lozenge was taken out, and the ungelatinized portion and the diameter of the gel layer (D obs) were measured, thereby calculating the gelation rate (G), as shown in Table 15 »Table 15 Results of the gel formation test. Test time (h) D obs (mm) G (X) Comparative prescription 2 0 8.0-(SR) 2 No change, 0 Example printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy 2 0 9. 0-2 5.4 ± 0.02 76.2 ± 0.3 (π = 3, average ± s · e) -34- The size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm). Employees' cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs. Printed A6 B6 V. Description of the invention (33) ⑶ Dog administration test The male beagle (η = 6) on a hunger strike for about 20 hours will take the tablet of Example 2 × 3 tablets (Pd 160mg) and the comparative prescription of 2 tablets × 2 tablets (Pd 160mg) and water 3Qb1-oral administration. Blood was collected over time and plasma drug concentrations were determined by HPLC / UV method (Table 16, Figure 13). Table 16 Pharmacokinetic parameters Formulation AUC 0-24 C max T max (ng · h / ml) (ng / ml) (h) Example 2 (Pd 160mg) 375.7 ± 89 · 3 52 · 9 ± 15.5 7.3 ± 3.5 Comparative prescription 2 (Pdl60mg) 125.0 ± 31.8 53 · 6 ± 12.5 1_3 ± 0.2 (n = 6, mean ± se) Test results in vitro dissolution test. Comparative prescription 2 (SR) showed approximately the same dissolution behavior as in Example 2. (Table 14), but the penetration rate (gelation rate) of water is very different (Table 15). As a result of oral administration of these preparations to dogs, the change in the drug concentration in the plasma at the time of administration in Example 2 was obviously persistent compared with that in the case of administration in Comparative Prescription 2. In addition, when the prescription 2 is administered, the drug concentration in the plasma is 2 hours after the preparation migrates to the lower part of the digestive tract, and the paper size is applicable to the Chinese National Standard (CNS) A4 specification (2) 0 X 297 mm) ---. --------------, 1 ------ install ------ '玎 ------ line (Please read the precautions on the back before filling this page ) A6 B6 V. Description of the invention (34) It is found that the drug is difficult to dissolve and absorb in the lower part of the digestive tract. In contrast, when administered in Example 2, the drug concentration in the plasma was maintained for 2 hours after migration to the lower part of the digestive tract, and it was clear that the drug in the lower part of the digestive tract was well dissolved and absorbed. Because the absorption time is entangled, the highest plasma drug concentration (C nax) at the time of administration in Example 2 is approximately equal to that at the time of administration of Comparative Prescription 2, but the A U C increases by about 3. Q times. Example 3 6 δ (replacement) 13 Xu Fang Bu (SR) 6 5 65 6 5

Pd T w e e η 8 0 CMEC PEG6000 P0LY0X3 0 3Pd T w e e η 8 0 CMEC PEG6000 P0LY0X3 0 3

Pd 15 速放部 （QR) 將鹽酸尼卡地平（Pd)，Tween80及CMEC溶在混合溶劑 (二氣甲烷/甲醇），用噴乾機來噴蓀乾燥。將噴乾品 與PEG6000及Polyox303混合後，用油壓機以打錠壓1噸 /杵打錠，得直徑8·5πιβ,每錠重量273mg (含QR, Pd 65ng)之錠劑（SR)。 次得作為速放部（QR),含有Pd 15mg之錠商K (請先閱讀背面之注意事項再塡寫本頁) 丨裝. 訂. .蜱| 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（35 ) 比較處方3 Pd T w e e η 8 0 CMEC POLYOX303 65 (重量份） 13 6 5 2 8.6Pd 15 Quick-Release Unit (QR) Nicardipine (Pd), Tween80, and CMEC are dissolved in a mixed solvent (methane / methanol) and spray-dried with a spray dryer. After the spray-dried product was mixed with PEG6000 and Polyox303, the tablet was pressed with a hydraulic press with a ton of 1 ton per pestle to obtain a tablet with a diameter of 8.5 μm and a tablet weight of 273 mg (including QR, Pd 65ng). Zide is the Quick Release Department (QR), containing the tablet manufacturer K of 15mg Pd (please read the precautions on the back before writing this page) 丨 Packing. Order.. Tick | Paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of invention (35) Comparative prescription 3 Pd T wee η 8 0 CMEC POLYOX303 65 (parts by weight) 13 6 5 2 8.6

徐放部（SR (請先閱讀背面之注意事項再填寫本頁)Xu Fang Bu (SR (Please read the notes on the back before filling out this page)

Pd 15 速放部（QR)Pd 15 Quick Release (QR)

TC-5E 將鹽酸尼卡地平（Pd), Tween80及CMEC溶在二氱甲烷 及甲醇混液，用噴乾機來噴霧乾燥。將噴乾品與Polyox 3 G 3混合後，用油壓機以打錠壓0.8噸/种打錠，得直徑 8.0咖，每錠171.6ng (含Pd 65mg)之錠劑（SR)。另將 Pd及TC-5E溶在二氣甲烷與甲醇之混液，用塗布機在SR (Pd 65mg)被覆速放部（QR, Pd 15ng),得每錠重量 1 9 4 · 1 in g 之錠劑（P d 8 0 m g )。 ⑴溶出試驗 試驗液採用日本藥典崩壞試驗法第2液，依 <日本藥典 溶出試驗法第2法（獎法）以獎轉速2 0 0 rpm進行試驗， 定時取樣而依U V法测定溶液中之P d。 經濟部中央標準局員工消費合作社印製 比較處方3 (SR)及實施例3 (SR)之溶出試驗結果如圖 1 4 〇 ⑵凝膠形成試驗 試驗液採用日本藥典崩壞試驗法第1液，依日本藥典 -37- 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） A6 _ B6_ 五、發明説明（36) 溶出試驗法第2法（奬法）以奬轉速2 5 r p B進行試驗。 2小時後取出錠劑，剝離凝膠層而測定未凝膠化部分之 重量（W obs),由此依下式2算出凝膠化率（G)，如表17 表17 凝膠形成試驗結果（η = 3，平均土 s . e .) (請先閲讀背而之注意事項再塡寫本頁) 製 劑 試驗時間（h ) W 〇 b s ( g ) G (%) 比較處方3 0 0.167 一 (SR) 2 0 · 1 5 3 ± 0 . 0 8 . 2 ± 1 . 4 實施例3 0 0.276 — (SR) 2 0 . 0 5 5 ± 0·4 7 9 · 6 ± 0 . 4 丨裝. 數式2 (W 〇 b s ) G ( % ) = ( 1 - —-) X 10 0 (W ini) W obs :試驗開始後、凝膠層剝離後之重量 W ini:試驗開始前之錠劑重量 (3)狗投予試驗 對絶食約20小時之雄小獵犬（η = 6)將實施例3之SR及 -3 8 _ 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） .絲. 經濟部中央標準局員工消費合作社印製 A6 _B6_ 五、發明説明（37 ) QR各2錠（Pd 160mg)及比較處方3 2錠（Pd 160mg)與 水3Qml—起經口投予。經時採血而依HPLC/UV法測定血 漿中藥物濃度（表18,圖15)。 表18 藥動力學參數 （n = 6,平均土 s.e.) 製劑 AUC 0-24 C max T max MRT (ng · h/ml) (ng/ml) (h) (h) 比較處方3 125.0± 31.8 53.6± 12·5 1. 3± 0. 2 2.4± 0.4 實施例8 54 7 . 1 ± 180.4 81 · 6± 14 · 8 3.9± 1 · 1 6.3± 1.0 ⑷狗解剖試驗 用絶食約2 0小時之雄小獵犬3隻。解剖之2 , 4及6小 時前，將各種製劑與水3〇ΠΙ—起經口投予，在戊基巴比 妥納之麻醉下解剖而脱血後，開腹而調査製劑之消化管 内之位置（表19) β另小腸部予以5等分，從上部起分 別為小腸1 , 2，3 , 4，5。 iln--------------,1------裝------tr------線 (請先閲讀背面之注意事項再塡寫本頁) 經濟部中央標準局R工消費合作社印製 -39- 本紙張尺度適用中國國家標準（CNS)甲4規格（2】0 X 297公釐） A6 B6 五、發明説明（38) (請先閲讀背面之注意事項再填寫本頁) 表19 消化管内之位置（小腸部為5等分） 狗 No . 2 小 時 4小時 6小時 比 較 處 方3 4 結 腸 結 腸 結 腸 5 結 賎 結 腸 結 腸 6 小 腸 1 結 腸 結 腸 實 施 例 3 4 小 腸 5 結 腸 結 腸 5 結 腸 結 腊 結 腸 6 小 腸 1 結 腸 結 腸 .装. .1T_ 試驗結果 在活體外溶出試驗，比較處方3 (SR)與賁施例3 (SR) 呈現大致同樣之溶出舉動（圖14),但水之浸入速度（ 凝膠化率）大不相同（表17)解剖實驗之結果，實施例 3及比較處方3呈大致同樣消化管移動（表19)。這些 製劑對狗經口投予之結果，與比較處方3投予時相較，實 施例3投予時之血漿中藥物濃度推移顯然為持缠性。另 經濟部中央標準局S工消費合作社印5衣 以物部 時藥下 小部管 2 下化 之管消 行化向 移消在 部在 ， 下知時 管得予 化，投 消少 3 向減例 劑著施 製顯實 ，度觀 時濃反 予物 〇 投藥收 3 中吸 方漿及 處血出 較，溶 比後難 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（39) 移行之2小時以後，仍雒持血漿中藥物濃度，顯然在消 化管下部之藥物溶出及吸收良好（圖15)。又因吸收時 間會持鑛，故實施例3投予時之最高血漿中藥物濃度 (C max)與比較處方3投予時者大致相等，但AUC則增大 約4 . 4倍（表18)。 實施例4 Pd PVP E 3 Ο Η C Ο - 6 Ο POLΥΟΧ303 滑澤劑 (請先閱讀背面之注意事嘈再填寫本頁) 8 0 ( Β g ) 3 2 16 2 4 0 4 將鹽酸尼卡地平（Pd)，PVP Κ30及HC0-60溶在甲醇， 而用流動層造粒機噴霧造粒於Polyox 303。於造粒品加 滑澤劑而予以混合及打錠，得直徑9.5咖，每錠372mg( 含Pd 80 mg)之錠劑。 實施例5 經濟部中央標準局員工消費合作社印製TC-5E Dissolves nicardipine hydrochloride (Pd), Tween80 and CMEC in a mixture of methylene chloride and methanol, and spray-dry with a spray dryer. After mixing the spray-dried product with Polyox 3 G 3, use an oil hydraulic machine to press the tablet at a rate of 0.8 ton / kind to obtain a tablet with a diameter of 8.0 and a tablet of 171.6ng (including 65mg of Pd) (SR). In addition, Pd and TC-5E were dissolved in a mixture of methane and methanol, and the rapid-release part (QR, Pd 15ng) was covered with a coating machine at SR (Pd 65mg) to obtain an ingot of 19.4 · 1 in g in weight. Agent (P d 80 mg). The dissolution test test solution uses the second liquid of the Japanese Pharmacopoeia disintegration test method. According to the second method of the Japanese Pharmacopoeia Dissolution Test Method (Prize Method), the test is performed at a prize speed of 200 rpm, and the solution is periodically sampled to determine the solution according to the UV method. Of P d. The dissolution test results of Comparative Formula 3 (SR) and Example 3 (SR) printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are shown in Fig. 14. The gel formation test test solution uses the first liquid of the Japanese Pharmacopoeia Collapse Test Method. According to the Japanese Pharmacopoeia-37- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 _ B6_ V. Description of the invention (36) Dissolution test method 2nd method (prize method) 5 rp B for testing. After 2 hours, the lozenge was taken out, the gel layer was peeled off, and the weight (W obs) of the ungelatinized portion was measured. From this, the gelation rate (G) was calculated according to the following formula 2, as shown in Table 17 and Table 17: Results of gel formation tests (Η = 3, average soil s. E.) (Please read the precautions before writing this page) Preparation test time (h) W 〇bs (g) G (%) Comparative prescription 3 0 0.167 One ( SR) 2 0 · 1 5 3 ± 0. 0 8. 2 ± 1. 4 Example 3 0 0.276 — (SR) 2 0. 0 5 5 ± 0 · 4 7 9 · 6 ± 0. 4 丨 installed. Number Formula 2 (W 〇bs) G (%) = (1-—-) X 10 0 (W ini) W obs: weight after the test is started and after the gel layer is peeled off W ini: the weight of the tablet before the test is started ( 3) Dog administration test For male beagles (η = 6) on a hunger strike for about 20 hours, the SR and -3 of Example 3 _ This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Silk. Printed by A6 _B6_ of the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (37) 2 tablets of QR (Pd 160mg) and 32 prescriptions (Pd 160mg) of water and 3Qml of water are administered orally. Blood was collected over time and the plasma drug concentration was determined by HPLC / UV method (Table 18, Figure 15). Table 18 Pharmacokinetic parameters (n = 6, average soil) Preparation AUC 0-24 C max T max MRT (ng · h / ml) (ng / ml) (h) (h) Comparative prescription 3 125.0 ± 31.8 53.6 ± 12 · 5 1. 3 ± 0.2 2 2.4 ± 0.4 Example 8 54 7. 1 ± 180.4 81 · 6 ± 14 · 8 3.9 ± 1 · 1 6.3 ± 1.0 绝 Hunger for dog dissection test for about 20 hours Three hounds. Two, four, and six hours before dissection, the various preparations were administered orally with water 30III. After dissection under pentyl barbituran anesthesia and bleeding, the abdomen was opened to investigate the position in the digestive tube of the preparation. (Table 19) β and the small intestine were divided into 5 equal parts, from the upper part to the small intestine 1, 2, 3, 4, and 5, respectively. iln --------------, 1 ------ install ------ tr ------ line (please read the precautions on the back before copying the copy Page) Printed by the Central Industry Bureau of the Ministry of Economic Affairs, R Industrial Consumer Cooperatives-39- This paper size applies to China National Standard (CNS) A4 specifications (2) 0 X 297 mm A6 B6 V. Description of the invention (38) (please first Read the notes on the back and fill in this page again) Table 19 Position in the digestive tract (small intestine is divided into 5 equal parts) Dog No. 2 hours 4 hours 6 hours comparative prescription 3 4 colon colon colon 5 crusted colon colon 6 small intestine 1 colon colon Example 3 4 Small intestine 5 Colon and colon 5 Colonized wax colon 6 Small intestine 1 Colon and colon. Packing .1T_ Test results in vitro dissolution test, comparing prescription 3 (SR) and 贲 Example 3 (SR) showed approximately the same dissolution The behavior (Figure 14), but the speed of infiltration of water (gelation rate) is very different (Table 17). As a result of anatomic experiments, Example 3 and Comparative Formula 3 showed approximately the same movement of the digestive tract (Table 19). As a result of orally administering these preparations to dogs, the change in plasma drug concentration at the time of administration in Example 3 was apparently persistent compared with that in the case of administration in Comparative Prescription 3. In addition, the Central Standards Bureau of the Ministry of Economic Affairs of the S Industry Consumer Cooperatives printed 5 clothes to the Ministry of Economic Affairs, the Ministry of Medicine, the Ministry of Management, the Ministry of Management, the Ministry of Management, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economic Affairs, the Ministry of Economics The reducing agent is applied to show the actual effect, and the concentration is reversed when it is viewed. 0 The medicine is collected. 3 The liquid is inhaled and the blood is discharged. After the dissolution ratio is difficult, this paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of the invention (39) Two hours after the transfer, the drug concentration in the plasma was still controlled, and the drug in the lower part of the digestive tract was clearly dissolved and absorbed well (Figure 15). Since the absorption time will hold the minerals, the highest plasma drug concentration (C max) at the time of administration in Example 3 was approximately equal to that at the time of administration of Comparative Prescription 3, but the AUC increased approximately 4.4 times (Table 18). Example 4 Pd PVP E 3 〇 Η C Ο-6 Ο POLΥ〇 × 303 slip agent (please read the cautions on the back before filling this page) 8 0 (Β g) 3 2 16 2 4 0 4 Will nicardipine hydrochloride (Pd), PVP K30 and HC0-60 were dissolved in methanol, and then spray-granulated with Polyox 303 using a fluidized bed granulator. The granulated product is added with a smoothing agent, mixed and beaten to obtain a tablet with a diameter of 9.5 and a tablet of 372 mg (containing Pd 80 mg). Example 5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Pd 80(mg) TC-5E 3 2 HC0-60 16 PEG6000 3 2 POLY 0X303 2 4 0 滑澤劑 8 流動化劑 4 -41 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 8 0 ( B g ) 32 3 2 3 2 384 11.2 A6 _B6_ 五、發明説明（4〇) 將鹽酸尼卡地平（Pd), TC-5E及HC0-60溶在水-甲醇1 :9混液，而噴霧乾燥後，加P〇lyox303，滑澤劑4 mg相 當量，而予以乾式造粒。於造粒品加滑澤劑4 ag相當量 及流動化劑，而予以混合及打錠，得直徑3.5βπι,每錠 4 1 2 m g ( P d 8 0 m g )之錠劑。 寅施例6 Pd T C - 5 E HC0-60 PEG6000 Polyox303 滑澤劑 流動化劑 將鹽酸尼卡地平（Pd), TC-5E, HC0-60及PEG6000溶在 水-甲醇混液（1: 9)而噴蓀乾烽後，加Poly 〇χ303,滑澤 劑5.6nig來乾式造粒。次加滑澤劑5.6ng及流動化劑而予 以混合及打錠，得直徑11则》,每錠576.8iog (含Pd 80oig ---^--------------I------裝------，玎------緯 (請先閲讀背面之注意事項再塡寫木頁) 經濟部中央標準局員工消費合作社印製 之錠劑。 施例7 Pd 8 0 ( m g ) T C - 5 E 64 Τ κ e e η 8 0 3 2 PEG6000 3 2 -4 2 - 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 五、發明説明（41 )Pd 80 (mg) TC-5E 3 2 HC0-60 16 PEG6000 3 2 POLY 0X303 2 4 0 Lubricant 8 Fluidizer 4 -41 This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 male) (Centi) 8 0 (B g) 32 3 2 3 2 384 11.2 A6 _B6_ 5. Description of the invention (40) Nicardipine hydrochloride (Pd), TC-5E and HC0-60 are dissolved in a 1: 9 mixture of water and methanol After spray drying, Polyox303 and 4 mg of lubricating agent were added to dry granulate. Add 4 ag equivalent amount of slip agent and fluidizing agent to the granulated product, and mix and beat the tablets to obtain tablets with a diameter of 3.5βπ and 4 12 m g (P d 80 m g) per tablet. Example 6 Pd TC-5 E HC0-60 PEG6000 Polyox303 slip agent fluidizer dissolving nicardipine hydrochloride (Pd), TC-5E, HC0-60 and PEG6000 in a water-methanol mixture (1: 9) and After spraying and drying, add Poly 〇χ303, smoothing agent 5.6nig to dry granulate. Add 5.6ng of smoothing agent and fluidizer to mix and beat ingots to get 11 diameters, 576.8iog per ingot (including Pd 80oig --- ^ -------------- I ------ loading ------, 玎 ------ wei (please read the notes on the back first, and then write the wooden page) The tablets printed by the cooperative of employees of the Central Standards Bureau of the Ministry of Economic Affairs Example 7 Pd 8 0 (mg) TC-5 E 64 Τ κ ee η 8 0 3 2 PEG6000 3 2 -4 2-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) A6 V. Description of Invention (41)

Polyox 303 3 6 0 滑澤劑 11.4 流動化劑 5.7 將鹽酸尼卡地平（Pd), TC-5E, Tween80溶在水-甲醇 混液（1: 9)而噴霧乾燥後，加PEG6000, Polyox303,滑 澤劑5 . 7mg來乾式造粒e次加滑澤_ 5 . 7mg及流動化劑而 予以混合及打錠，得直徑11 mm,每錠585. 1 mg (含Pd 80 mg)之錠劑β 實施例8 將Pd及TC-5E溶在水-甲醇混液（1: 9)，而用塗布機將 速放部（Pd 20 mg)塗在實施例7 (Pd 80ing),得毎錠625.1 in g 之錠劑（P d 1 0 0 m g )。 實施例9 將Pd及HPC-SL溶在甲醇，而用塗布機將放部（Pd 2〇fflg) 塗在實施例7 (Pd 80mg),得每錠625.1mg之錠劑（Pd 1 0 0 hi g ) 〇 實施例10 ----；----------------------裝------訂------線 (請先閱讀背面之注意事項再塡寫本頁) 經濟部中央標準局員工消費合作社印製Polyox 303 3 6 0 Lubricant 11.4 Fluidizer 5.7 Dissolve nicardipine hydrochloride (Pd), TC-5E, Tween80 in a water-methanol mixture (1: 9) and spray dry, then add PEG6000, Polyox303, luster 5.7mg of dry granulation e times plus slippery _5.7mg and fluidizer were mixed and tableted to obtain 11 mm diameter, 585.1 mg (including Pd 80 mg) tablets β implementation Example 8 Pd and TC-5E were dissolved in a water-methanol mixed solution (1: 9), and a quick-release part (Pd 20 mg) was applied to Example 7 (Pd 80ing) with a coater to obtain 625.1 in g of gadolinium ingot. Lozenges (P d 100 mg). Example 9 Pd and HPC-SL were dissolved in methanol, and the discharge part (Pd 2fflg) was applied to Example 7 (Pd 80 mg) with a coater to obtain 625.1 mg of each tablet (Pd 1 0 0 hi g) 〇Example 10 ----; ---------------------- installation ------ order ------ line (please (Read the notes on the back before writing this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

Pd 8 0 ( m g ) T C - 5 E 6 4 H C 0 - 4 0 32 P E G 6 0 0 0 4 8 P0LY0X303 3 4 4 滑澤劑 11.4 流動化劑 5.7 -4 3- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） 經濟部中央標準局R工消費合作社印製 A6 B6_ 五、發明説明（42) 將P d，T C - 5 E及H C 0 - 4 0溶在水-甲醇混液（1 : 9 )而噴霧 乾燥後，PEG6GQ0，Poly οχ303,滑澤劑5_7mg來乾式造 粒。次加滑澤劑5.7mg及流動化劑而予以混合及打錠， 得直徑11_，每錠585.1mg (含Pd 80mg)之錠劑。 實施例1 1 Pd T C - 5 E 'HC0-40 P E G 6 0 0 0 Polyox303 滑澤劑 流動化劑 將Pd, TC-5E,及HC0-40溶在水-甲醇混液（1: 9)而噴 蓀乾燥後，PEG600Q, Polyox3D3,滑澤劑5.7ng來乾式 造粒。次加滑澤劑5 . 7mg及流動化劑而予以混合及打錠 ,得直徑11酬，每錠585.1mg (含Pd lOOmg)之錠劑。 ⑴溶出試驗 試驗液採用曰本藥典崩壊試驗法第1液，依日本藥典 溶出試驗法第2法（奬法）以槳轉速2 0 0 rpiii進行試驗， 定時取樣而依U V法測定溶液中之P d。 實施例4及5之溶出試驗結果如圖16。 實施例6, 7及10之溶出試驗結果如圖17。 (2)狗投予試驗 -4 4 - 100 (mg) 80 4 0 4 8 3 0 0 11.4 (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)甲4規格（210 X 297公釐） A6 __B6_ 五 '發明説明（43) (請先閱讀背面之注意事項再®寫本頁) 對雄小獵犬（n = 6)將2錠實施例5或2錠實施例6每 曰1次連缠投予4曰。經時採血而依Η P L C / ϋ V法測定血 漿中藥物濃度。 試驗結果 實施例5及6均以毎日1次之投予而呈現高C24h值（ 投予24小時後之血中濃度）及高生物學利用率（AUC)。 實施例1 2 DF 37.5(mg) PEG6000 37.5Pd 8 0 (mg) TC-5 E 6 4 HC 0-4 0 32 PEG 6 0 0 0 4 8 P0LY0X303 3 4 4 Lubricant 11.4 Fluidizer 5.7 -4 3-This paper size applies to Chinese National Standard (CNS ) A4 specifications (210 X 297 mm) A6 B6_ printed by R Industrial Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (42) P d, TC-5 E and HC 0-4 0 are dissolved in water-methanol After mixing the solution (1: 9) and spray-drying, PEG6GQ0, Poly οχ303, and smoothing agent 5-7 mg were used for dry granulation. Add 5.7mg of lubricating agent and fluidizing agent, mix and beat the tablets, to obtain a tablet with a diameter of 11_, 585.1mg (including Pd 80mg) per tablet. Example 1 1 Pd TC-5 E 'HC0-40 PEG 6 0 0 0 Polyox303 slip agent fluidizer Pd, TC-5E, and HC0-40 were dissolved in a water-methanol mixture (1: 9) and sprayed. After drying, PEG600Q, Polyox3D3, and lubricating agent 5.7ng were used to dry granulate. Add 5.7mg of lubricating agent and fluidizing agent to mix and beat the tablets, and get 11 diameters, 585.1mg (including Pd 100mg) tablets per tablet. The dissolution test test solution uses the first liquid of the Japanese Pharmacopoeia disintegration test method, according to the Japanese Pharmacopoeia Dissolution Test Method 2 (reward method). The test is performed at a paddle speed of 200 rpiii. Periodic sampling is used to determine the P in the solution according to the UV method. d. The dissolution test results of Examples 4 and 5 are shown in FIG. 16. The dissolution test results of Examples 6, 7 and 10 are shown in FIG. 17. (2) Dog dosing test-4 4-100 (mg) 80 4 0 4 8 3 0 0 11.4 (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) A6 __B6_ Five 'invention description (43) (Please read the precautions on the back before writing this page) For male beagle (n = 6) will be 2 or 5 6 once every day to 4 days. Blood was collected over time and the drug concentration in blood plasma was measured by the P L C / ϋ V method. Test results Both Examples 5 and 6 showed high C24h value (blood concentration after 24 hours of administration) and high biological utilization rate (AUC) by the administration of the next day. Example 1 2 DF 37.5 (mg) PEG6000 37.5

Polyox303 75.0 將二氣芬納〇?)，？£66000及？〇17(^ 303在乳缽中混合 ，而用油壓機以打錠壓1噸/杵打錠，得直徑7 mm,每 錠 150mg (DF 37.5mg)之錠劑。 比較處方4 DF 37 · 5 (mg)Polyox303 75.0 will diqi Fenner 〇?) ,? £ 66000 and? 〇17 (^ 303 was mixed in a mortar, and 1 ton per pestle was beaten with an oil press to obtain tablets with a diameter of 7 mm and 150 mg (DF 37.5 mg) per tablet. Comparative prescription 4 DF 37 · 5 ( mg)

Polyox303 75.0 將DF及Polyox303在乳缽中混合，而用油壓機以打錠 壓1噸/杵打錠，得直徑6·0ιμ，毎錠112.5mg (含DF 37 . 5mg)之錠劑。 ⑴溶出試驗 經濟部中央標準局員工消費合作社印製 試驗液採用日本藥典崩壊試驗法第2液，依日本藥典 溶出試驗法第2法（奬法）試驗。定時取樣而依U V法測 定溶液中之D F (圖1 8 )。 -45- 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） A6 _ ___B6_ 五、發明説明（44 ) ⑵凝膠形成試驗 試驗液採用日本藥典崩壞試驗法第2液，依日本藥典 溶出試驗法第2法（奬法）以槳轉速2 5 Γ p m進行試驗。 每2小時取出錠，測定未凝膠化部分之直徑（D 〇 b s ), 由此算出凝膠化率（G),如表20。 表20 凝膠形成試驗結果（n = 3,平均土 s.e.) 犬37 獵 F 小(D 雄 4 之方 時處 小較 驗20比 試約及 予食 } 投絶mg 狗對5 ⑶37 服 F D Π {起 121 例alg 施30 實水 將與 ----：--------------------I-裝------.玎-------線-- (請先閲讀背面之注意Ϋ項再填寫本頁) 依 而 。 血 } 採19 時圖 經 ， 表 /f\ 度 濃 物 藥 中 漿 血 定 法 經濟部中央標準局員工消費合作杜印製 製劑 試驗時間 G (h) (% ) 實施例12 2 88 . 2 ± 1 . 1 比較處方4 2 37.0±4.6 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 _ B6 五、發明説明（45) (請先閱讀背面之注意事項再填寫本頁) 表2 1 經口投與（絶食）試驗 製劑 AUC 0-12 C max T max (n g · h/m 1 ) (ng/ml) ( h) 比較處方 4 5 0 5 2 ± 1 3 5 7 1 1 8 8 ±147 1.7±0.6 實施例 12· 8537±1941 1381±222 3,0±1.3 (n=5,平均土 s.e.) 實驗結果 - 在活體内溶出試駿，實施例12與比較處方4呈現大致 同樣之溶出舉動（圖18)，但水之浸入速度（凝膠化率 )大不相同（表20)。這些製劑對狗經口投予之結果， 與比較處方4投予時相較，實施例12投予時之血漿中藥 物濃度推移顯然為持鑛性（圖19)。另比較處方4比較 ,實施例12投予時之AUC增大約1.7倍（表21),也即對 酸性藥物之二氛芬鈉也因應用本發明而確認在消化管下 部_物良好地溶出及吸收。 經濟部中央標準局員工消費合作社印製 施例13 D F 7 5 ( mg) PEG6000 7 5 Polyox303 15 0 -47- 本紙張又度適用中國國家標準（CNS)甲4規格（210 X 297公釐） A6 B6 五、發明説明（46) 將二氛芬納（DF), PEG6000及Polyox303在乳鉢中混合 ,而用油壓機以打錠壓1噸/杵打錠，得直徑8·5ΒΒ1， 每錠3fl0mg (含DF75mg)之錠剤β 實施例14 DF (dichlorofen-Na) 7 5 ( m g) PEG6000 75 Polyox303 300 將二氛芬納（DF), PEG6000及Polyox303在乳缽中混合 ,而用油壓機以打錠壓1噸/杵打錠，得直徑9.5 Β», 每錠45flBg (含DF 75Bg)之錠劑β 實施例1 5 法莫地 J (famotidine) 4 0 ( m g) PEG6000 30 P0LY0X303 150 滑澤劑 2 將法莫地丁，PEG 6000，Poly〇x303及滑澤剤混合後 ，'打錠而得直徑8.0mm,每錠222mg (含法其地丁 40mg) 之錠劑〇 實施例1 6 鹽.酸巴尼地平（barnidipin) (請先閱讀背而之注意事項再填寫本頁) 丨裝. -绵· 經濟部中央標準屬員工消費合作社印製 TC- 5E HC0-40 P E G 2 0 0 0 0 1 5 ( m g ) 30 5 4 0 48- 未紙張尺度適用中固國家標準（CNS)甲4規格（210 X 297公釐） 經濟部t央標準局貝工消費合作社印製 A6 B6_ 五、發明説明（47) P0LY0X303 207 滑澤劑 3 將鹽酸巴尼地平，TC-5E及HC0-40溶在水甲醇混液（ 1:9)。9混合？£620000及？〇17(^303,而用流動層造 粒機將溶解液噴霧造粒於混合品上。乾燥後，混合滑澤 劑而打錠，得直徑9.0mm,毎錠300nig (含鹽酸巴尼地平 1 5mg)之錠劑。 實施例1 7 •鹽酸阿莫 士拉羅（amosulalol) 4 0(m g) 普羅尼克（Pluronic) F68 40Polyox303 75.0 DF and Polyox303 were mixed in a mortar, and the tablet was pressed with a hydraulic machine at a rate of 1 ton per pestle to obtain a tablet having a diameter of 6.0 μm and a osmium tablet of 112.5 mg (containing 37.5 mg of DF). Dissolution test Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics The test solution uses the second liquid of the Japanese Pharmacopoeia disintegration test method, which is tested according to the second method (award method) of the Japanese Pharmacopoeia dissolution test method. Take regular samples and determine the D F in the solution according to the U V method (Figure 18). -45- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 _ ___B6_ V. Description of the invention (44) ⑵The gel formation test test solution uses the second liquid of the Japanese Pharmacopoeia Collapse Test Method According to the second method (award method) of the Japanese Pharmacopoeia dissolution test method, the test was performed at a paddle speed of 25 Γ pm. The ingot was taken out every 2 hours, and the diameter (Dob s) of the non-gelatinized portion was measured to calculate the gelation ratio (G), as shown in Table 20. Table 20 Results of gel formation test (n = 3, average soil se) Dog 37 hunting F small (D male 4 squares all the time compared with the test 20 comparison and feeding)} absolute mg dog pair 5 ⑶37 serving FD Π { From 121 cases of alg application of 30 solid water will be ----: -------------------- I-loading --------. 玎 ---- --- line-- (please read the note on the back before filling this page). Blood} Collected at 19 o'clock, Table / f \ Degrees of concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, concentration, blood, blood concentration, etc. Cooperative Du printed preparation test time G (h) (%) Example 12 2 88. 2 ± 1.1 Comparison formula 4 2 37.0 ± 4.6 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297) (%) A6 _ B6 V. Description of the invention (45) (Please read the notes on the back before filling this page) Table 2 1 Oral administration (hunger strike) test preparation AUC 0-12 C max T max (ng · h / m 1) (ng / ml) (h) Comparative prescription 4 5 0 5 2 ± 1 3 5 7 1 1 8 8 ± 147 1.7 ± 0.6 Example 12 8537 ± 1941 1381 ± 222 3, 0 ± 1.3 (n = 5, average soil se) Experimental results-Dissolution test in vivo, Example 12 and Comparative Formula 4 show approximately the same (Figure 18), but the rate of infiltration of water (gelation rate) is very different (Table 20). The results of oral administration of these preparations to dogs are compared with those of Comparative Prescription 4 administration, Example 12 The change in the concentration of the drug in the plasma at the time of administration is obviously mineral-holding (Figure 19). In addition, when comparing the prescription 4, the AUC of Example 12 was about 1.7 times higher when administered (Table 21), which is the second atmosphere for acid drugs. The application of the present invention also confirmed good dissolution and absorption in the lower part of the digestive tract. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Example 13 DF 7 5 (mg) PEG6000 7 5 Polyox303 15 0 -47- present The paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A6 B6 V. Description of the invention (46) The two atmosphere Fenner (DF), PEG6000 and Polyox303 are mixed in a mortar, and the oil press is used to The ingot was pressed at 1 ton / penetrate to obtain a diameter of 8.5B1. Each ingot was 3fl0mg (containing DF75mg) ingot 剤 β. Example 14 DF (dichlorofen-Na) 7 5 (mg) PEG6000 75 Polyox303 300 DF), PEG6000 and Polyox303 are mixed in a mortar, and the ingot is pressed with a hydraulic press at a rate of 1 ton per pestle to obtain an ingot. Diameter 9.5 B », 45 flBg (containing DF 75Bg) tablets β each Example 15 5 famotidine 4 (mg) PEG6000 30 P0LY0X303 150 slip agent 2 famotidine, PEG 6000, After mixing Poly〇x303 and Takisawa tincture, 'to obtain tablets with a diameter of 8.0 mm, each tablet contains 222 mg (containing 40 mg of fazedidol). Example 16 Salt. Barnidipin (please first Read the precautions on the back and fill in this page) 丨 Packing.-Cotton · Printed by the Central Standard Department of the Ministry of Economic Affairs Consumer Cooperatives TC-5E HC0-40 PEG 2 0 0 0 0 1 5 (mg) 30 5 4 0 48- The paper size is applicable to the National Solid State Standard (CNS) A4 specification (210 X 297 mm) Printed by the Ministry of Economic Affairs and the Central Bureau of Standards, printed by the Bayer Consumer Cooperative A6 B6_ V. Description of the invention (47) P0LY0X303 207 Slipper 3 Hydrochloric acid Banidipine, TC-5E and HC0-40 were dissolved in a water-methanol mixture (1: 9). 9 mixed? £ 620000 and? 〇17 (^ 303, and the solution was spray-granulated on the mixed product with a fluidized bed granulator. After drying, the lubricant was mixed with a lubricating agent to form a tablet. 5mg) lozenges. Example 17 • amosulalol hydrochloride (amosulalol) 4 0 (mg) Pluronic F68 40

Polyox303 196 滑澤劑 4 將鹽酸阿莫士拉羅，普羅尼克F 6 8 , Ρ ο 1 y ο x 3 Q 3及滑澤 劑混合粉碎後，予以乾燥造粒而打錠，得直徑8. 5mi,每 錠2 8 Q π g (含鹽酸阿莫士拉羅4 Q m g )之錠劑β 實施例1 8 鹽酸坦 士羅新（tamsulocin) 0 . 2 ( m g) D -花楸醇 17.85mi Polyox303 196 slip agent 4 will be amoxilarol hydrochloride, Pronike F 6 8, ρ ο 1 y ο x 3 Q 3 and the slip agent after mixing and pulverizing, and then dried and granulated to obtain tablets with a diameter of 8. 5mi Tablets of 2 8 Q π g (containing 4 Q mg of amoxilarol hydrochloride) per tablet. Example 1 8 Tamsulocin hydrochloride 0.2 (mg) D-anthocyanin 17.8

Polyox VSR N-60K 180 滑澤劑 2 將鹽酸坦士羅新，D -花楸醇及PE0(Polyox WSR N-60K) 用乙醇予以濕式造粒而乾燥後，加滑澤劑而混合打錠， 得直徑8咖，毎錠200mg (含鹽酸坦士羅新0.2iag)之錠 -49- 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐） ----;-------------I------裝------·玎-------線. {請先閲讀背面之注意事項再填寫本頁) A6 B6 五、發明説明（48) 劑。 實施例1 9 經濟部中央標準局員工消費合作社印絮 鹽 酸 印 得 羅 0咢 阱 (i n d lei 0 X :a 2 :i π e ) 6 0 ( m g ) 白 糖 3 7 HPMC (9 0 SH30 0 0 〇 ) 180 滑 澤 劑 3 將 鹽 酸 印 得 羅 U咢 阱 f 白 糖 » HPMC 及 滑澤劑混合 後 9 予 以 乾 式 造 粒 而 打 錠 > 得 直 徑 9fltio , 每錠28 0 in g (含 鹽 酸 印 得 羅 It咢 阱 6 0 B g ) 之 錠 劑 〇 實 施 例 2 0 反 丁 烯 二 酸 賀 莫 跌 羅 (f 〇 r a ο t e _ r ο 1.) 0 . 16( a g ) 無 水 麥 芽 糖 47 . 84 Ca r b op ο 1 9 4 0 10 0 滑 澤 劑 2 將 反 丁 烯 二 酸 賀 莫 跌 羅 9 無 水 麥芽 糖， Car bop o 1 940 及 滑 澤 劑 混 合 後 9 打 錠 而 得 直 徑 7 nn , 每 錠 150mg ( 含 反 丁 烯 二 酸 賀 莫 跌 羅 0 . 2 m g) 之錠劑。 實 施 例 2 1 AAP 100 (mg) PEG6 0 0 0 200 PE 0 (P ο 1 y 〇 X WS R N - 60K) 3 0 0 將 乙 醯 胺 芬 (AAP )， PEG60 〇〇及 P E0 (Po lyox WSR N- 60 K平均分子量2 0 0 萬 ) 在 乳 鉢 中 混合 而用油壓機 以 打 錠 -50- 本紙張^度適用中國國家標準（CNS)甲4规格（210 X 297公釐） (請先閲讀背面之注意事項再場寫本頁) 丨裝. 訂. 經濟部中央標準局員工消費合作社印製 A6 B6_五、發明説明（48) 壓1噸/杵打錠，得直徑11mm,每錠600mg (含AAP 100 mg)之錠劑。 fcfc較例5 AAP 100(mg) PEO (Polyox WSR N-60K) 300 將AAP及PEO (polyox WSR N-60K)在乳缽中混合而用 油壓機以打錠壓1噸/杵打錠，得直徑9 nm,毎錠400 ng (含 AAPlOOmg)之錠劑 β ⑴溶出試驗 試驗液採用日本藥典崩壞試驗法第2液，依日本藥典 溶出試驗法第2法（槳法）以奬轉逢2 0 0 r ρ Β進行試驗。 定時取樣依UV法測定溶液中之AAP。 (2)凝膠形成試驗 試驗液探用日本藥典崩壞試驗法第2液，依日本藥典 溶出試驗法第2法（獎法）以奬轉速25rpm進行試驗。 每2小時後取出錠劑，測定未凝膠化部分之直徑（D obs) ，由此算出凝膠化率（G)。 ⑶狗投予試驗 對絶食約2 0小時之雄小獵犬（η = 6 )將比較例5 ( A A P lOOmg)及實施例21 (AAP 100mg)與水30ml—起口服。經 時採血而依HPLC/UV法測定血漿中藥物濃度。 試驗結果 在活體外溶出試驗，比較例5與赉施例21呈現大致相 -5 1 - ”---.-------------I------裝------，玎------, (請先閲讀t面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4規格（2]0 X 297公釐） 經濟部中央標準局員工消費合作社印製 A6 B6__ 五、發明説明（49) 同溶出舉動，但在添加親水基劑之實施例21呈現比之較 例5較大'的凝膠化率。將這些製劑對狗口服之結果，與 比較例5相較，實施例21之錠投予時之血中濃度推移顯 然為持澳性》實施例21投予時之最高血漿中未變化濃度 (C max)與比較例5之錠投予時大致相等，但AUC, MRT 增大。又實施例21投予時之血中濃度至投予12小時後仍 很高。 産業上之利用可能性 本發明製劑能在滞留消化管上部期間吸收水分而大致 完全凝膠化，邊浸蝕製劑表面，邊移往消化管下部，更 由浸蝕缠放出藥物。故在水分少之結腸仍行良好且持缠 之藥物放出長達6〜18小時（加上在消化管上部之放出 時間可達1 2〜24小時），得以持缠放出藥物，達成安定 之藥物血中濃度。 以往之徐放性製劑因只能在消化管上部放出藥物，故 放出時間頂多6小時而已，其後乃由藥物本身之生物學 半衰期之長度而延長血中濃度。本發明製劑即為延長藥 物放出時間，故對於以往認為困難之生物學半衰期短之 藥劑也能逹成超出12小時之持缠性藥物血中濃度。 故本發明製劑不但能使藥物之效力持鑛而減少投予次 數，且能抑制血中藥物濃度之急速上昇而減輕副作用， 又能保持一定之血中藥物濃度等優點。 如前述實施例所示，本發明對如中性藥物乙醯胺芬， -5 2 - (請先閱讀背西之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)甲4规格（210 X 297公釐） 五、發明説明（50) A6 B6 物之 藥高 何性 任用 等泛 納為 芬 ， 氩物 二物 物之 藥物 性藥 酸拘 及不 平故 地 〇 卡間 尼時 酸鑛 鹽持 0 物長術 藥延技 性能劑 $ 均製 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)甲4規格（210 X 297公釐）Polyox VSR N-60K 180 Lubricant 2 Wet granulate tansulosin hydrochloride, D-anthopol and PE0 (Polyox WSR N-60K) with ethanol and dry, then add lubricating agent and mix into tablets There are 8 tablets with a diameter of 200mg and 200mg of tartarium hydrochloride (containing 0.2iag of tansulosin hydrochloride) -49- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----;- ------------ I ------ install ------ · 玎 ------- line. (Please read the precautions on the back before filling this page) A6 B6 V. Description of the invention (48) Agent. Example 1 9 The Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China, Printed Hydrochloride and Indello Hydrochloride (ind lei 0 X: a 2: i π e) 6 0 (mg) White sugar 3 7 HPMC (9 0 SH30 0 0 〇 ) 180 Slip agent 3 Induro hydrochloride hydrochloride f white sugar »HPMC and slip agent 9 mixed with dry granulation and ingots > to obtain a diameter of 9 fltio, each ingot 28 0 in g (containing indello hydrochloride) It is trapped with 60 Bg). Example 20 0 fumarate fumarate (f 〇 ο te _ r ο 1.) 0. 16 (ag) anhydrous maltose 47. 84 Ca rb op ο 1 9 4 0 10 0 Smoothing agent 2 Mix the fumarate fumaric acid 9 anhydrous maltose, Car bop o 1 940 and the smoothing agent 9 tablets to obtain a diameter of 7 nn, each tablet 150mg ( Lozenges containing fumarate fumarate (0.2 mg). Example 2 1 AAP 100 (mg) PEG6 0 0 0 200 PE 0 (P ο 1 y OX WS RN-60K) 3 0 0 Acetaminophen (AAP), PEG60 〇〇 and P E0 (Polyox WSR N- 60 K average molecular weight 2 million) Mix in a mortar and use an oil press to beat ingots 50- This paper is compliant with China National Standard (CNS) A4 specifications (210 X 297 mm) (please read the back first) (Notes on this page will be reprinted here) 丨 Packing. Order. Printed by A6 B6_, Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs V. Invention Description (48) Pressing 1 ton per pestle to obtain an ingot with a diameter of 11mm and 600mg per ingot ( Lozenges containing AAP 100 mg). fcfc Comparative Example 5 AAP 100 (mg) PEO (Polyox WSR N-60K) 300 AAP and PEO (polyox WSR N-60K) were mixed in a mortar, and a 1 ton per pestle was punched with an oil press to obtain a diameter. 9 nm, osmium tablets 400 ng (containing AAPIOOmg), osmium beta osmium dissolution test test solution uses the second liquid of the Japanese Pharmacopoeia disintegration test method, according to the second method (paddle method) of the Japanese pharmacopoeia dissolution test method, with a reward of 20 0 r ρ Β was tested. The AAP in solution was determined by regular sampling according to UV method. (2) Gel formation test The second solution of the Japanese Pharmacopoeia disintegration test method was used for the test solution test, and the test was performed at a prize speed of 25 rpm in accordance with the second method of the dissolution test method of the Japanese Pharmacopoeia (prize method). After 2 hours, the tablets were taken out, and the diameter (D obs) of the non-gelatinized portion was measured to calculate the gelation rate (G). (3) Dog administration test For a male beagle (η = 6) on a fast for approximately 20 hours, Comparative Example 5 (A AP 100 mg) and Example 21 (AAP 100 mg) were orally administered with 30 ml of water. Blood was collected over time and the plasma drug concentration was determined by HPLC / UV method. The results of the dissolution test in vitro showed that Comparative Example 5 and Example 21 were approximately the same as -5 1-"---.------------ I ------ pack- -----, 玎 ------, (Please read the notes on the t side before writing this page) This paper size is applicable to China National Standard (CNS) A4 specifications (2) 0 X 297 mm ) A6 B6 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (49) The same dissolution behavior, but in Example 21 with the addition of a hydrophilic base, the gelation rate is larger than that of Example 5. As a result of these preparations being orally administered to dogs, compared with Comparative Example 5, the change in blood concentration at the time of administration of the tablet of Example 21 was obviously sustained. The highest unchanged plasma concentration (C max at the time of administration of Example 21) ) Is about the same as that of Comparative Example 5, but the AUC and MRT increase. The blood concentration at the time of Example 21 was still high after 12 hours of administration. Industrial Applicability The preparation of the present invention It can absorb water during the retention of the upper part of the digestive tract and almost completely gelate, while eroding the surface of the preparation, it moves to the lower part of the digestive tract, and releases the drug by the entanglement. Therefore, the colon with less water The release of the drug which is still good and entangled is up to 6-18 hours (plus the release time on the upper part of the digestive tract can reach 12 to 24 hours), and the drug can be released and held to achieve a stable blood concentration of the drug. The Xufang preparation can only release the drug in the upper part of the digestive tract, so the release time is at most 6 hours, and then the blood concentration is prolonged by the length of the biological half-life of the drug itself. The preparation of the invention is to extend the release time of the drug Therefore, it is also possible to make the blood concentration of the entangled drug that exceeds 12 hours for the drug with a short biological half-life that was previously considered difficult. Therefore, the preparation of the present invention can not only reduce the number of administrations, but also suppress the number of administrations. The rapid increase in blood drug concentration reduces side effects, while maintaining a certain blood drug concentration, etc. As shown in the previous examples, the present invention is a neutral drug such as acetamide, -5 2-(Please read first Note on the back of the West, please fill out this page again) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) V. Description of the invention (50) A6 B6 Wait for ubiquitin to be a fen, argon two-drug substance, medicinal acid, and injustice. 0 carnitine acid mineral salt holding 0 substance long-acting medicine extended performance agent. $ Homogeneous (please read the precautions on the back first) (Fill in this page) The paper size printed by the Employees' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs applies to China National Standard (CNS) A4 specifications (210 X 297 mm)

Claims (1)

89^2. Ί·正 月 a89 ^ 2. Ί · 月 a 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 第8210*75 72號「口服用水膠體徐放性醫藥錠劑」專利案 (89年2月25日修正） 六申請專利範圍： 1. 一種口服用水膠體徐放性醫藥錠劑，係由至少⑴製劑 全體之85重量％以下之一種以上藥物，⑵製劑全體之 5~S0重量％—種或二種以上具有使基劑1克溶解所需 之水量爲4rol以下之溶解性之選自聚乙二醇，聚乙烯 吡咯啶酮，D -花楸醇，木糖醇，白糖，無水麥芽糖， D -果糖，聚葡糖，葡荀糖，聚氧乙烯硬化蓖麻油，聚 氧乙烯聚氧丙二醇，聚氧乙烯花楸醣高脂肪酸酯，氯 化鈉，氯化鎂，檸檬酸，酒石酸，甘胺酸，/5·丙胺 酸，鹽酸離胺酸，葡甲胺之一種或二種以上親水性基 劑，及⑶製劑全體之重量％平均分子量200萬 以上，或1%水溶液（25 °C)之粘度爲10 00 cps以上者之 一種或二種以上物之高分子物質：聚乙烯氧化物，羥 丙基甲基纖維素，羧甲基纖維素鈉、羥乙基纖維素’ 羧乙烯基聚合物所組成之醫藥組成物均勻混合來打錠 而成。 2. 如申請專利範圍第1項之口服用水膠體徐放性醫藥錠 劑，其中親水性基劑爲聚乙二醇或白糖。 3. 如申請專利範圍第2項之口服用水膠體徐放性醫藥錠 劑，其中親水性基劑爲聚乙二醇。 4. 如申請專利範圍第1項之口服用水膠體徐放性醫藥錠 劑，其中高分子物質爲含至少一種聚乙烯氧化物。 本紙張尺度適用中國國家操準（CNS > A4规格（210X297公釐） # 0 ^^1 1^— —^1 ^^1 1^1 m ^^1 —II I ^ n n I H ^^1 ^^1 ..:-.¾- i (請先閱讀背面之注f項再壤寫本頁) 89^2. Ί·正 月 aPrinted by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Patent Application No. 8210 * 75 No. 72 "Oral Water Colloid Xufang Pharmaceutical Tablets" (Amended on February 25, 89) Six. Patent Application Scope: 1. An oral hydrocolloid radioactive medicinal lozenge is composed of at least 8% by weight or less of the whole tincture preparation, and 5 to S0% by weight of the whole tincture preparation—one or two kinds having a base for dissolving 1 gram of the base agent. The solubility required for the amount of water below 4rol is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-anhydrol, xylitol, white sugar, anhydrous maltose, D-fructose, polyglucose, glucomannan, Polyoxyethylene hardened castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene anthosaccharide high fatty acid ester, sodium chloride, magnesium chloride, citric acid, tartaric acid, glycine, / 5 · alanine, hydrochloric acid lysine , One or two or more hydrophilic bases of meglumine, and one or two of the weight percent average molecular weight of the whole preparation of more than 2 million, or the viscosity of a 1% aqueous solution (25 ° C) of more than 100,000 cps Macromolecular substances of the above: poly A pharmaceutical composition composed of ethylene oxide, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose 'carboxyvinyl polymer is uniformly mixed to form a tablet. 2. For example, the oral hydrocolloid slow-release medicinal tablet in the scope of patent application, wherein the hydrophilic base is polyethylene glycol or sugar. 3. For example, the oral hydrocolloid slow-release medicinal tablet in the scope of patent application, wherein the hydrophilic base is polyethylene glycol. 4. For example, the oral hydrocolloid radioactive medicinal tablet in the scope of patent application, wherein the polymer substance contains at least one polyethylene oxide. This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) # 0 ^^ 1 1 ^ — — ^ 1 ^^ 1 1 ^ 1 m ^^ 1 —II I ^ nn IH ^^ 1 ^ ^ 1 ..:-. ¾- i (Please read the note f on the back before writing this page) 89 ^ 2. Ί · 月 月 a 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 第8210*75 72號「口服用水膠體徐放性醫藥錠劑」專利案 (89年2月25日修正） 六申請專利範圍： 1. 一種口服用水膠體徐放性醫藥錠劑，係由至少⑴製劑 全體之85重量％以下之一種以上藥物，⑵製劑全體之 5~S0重量％—種或二種以上具有使基劑1克溶解所需 之水量爲4rol以下之溶解性之選自聚乙二醇，聚乙烯 吡咯啶酮，D -花楸醇，木糖醇，白糖，無水麥芽糖， D -果糖，聚葡糖，葡荀糖，聚氧乙烯硬化蓖麻油，聚 氧乙烯聚氧丙二醇，聚氧乙烯花楸醣高脂肪酸酯，氯 化鈉，氯化鎂，檸檬酸，酒石酸，甘胺酸，/5·丙胺 酸，鹽酸離胺酸，葡甲胺之一種或二種以上親水性基 劑，及⑶製劑全體之重量％平均分子量200萬 以上，或1%水溶液（25 °C)之粘度爲10 00 cps以上者之 一種或二種以上物之高分子物質：聚乙烯氧化物，羥 丙基甲基纖維素，羧甲基纖維素鈉、羥乙基纖維素’ 羧乙烯基聚合物所組成之醫藥組成物均勻混合來打錠 而成。 2. 如申請專利範圍第1項之口服用水膠體徐放性醫藥錠 劑，其中親水性基劑爲聚乙二醇或白糖。 3. 如申請專利範圍第2項之口服用水膠體徐放性醫藥錠 劑，其中親水性基劑爲聚乙二醇。 4. 如申請專利範圍第1項之口服用水膠體徐放性醫藥錠 劑，其中高分子物質爲含至少一種聚乙烯氧化物。 本紙張尺度適用中國國家操準（CNS > A4规格（210X297公釐） # 0 ^^1 1^— —^1 ^^1 1^1 m ^^1 —II I ^ n n I H ^^1 ^^1 ..:-.¾- i (請先閱讀背面之注f項再壤寫本頁) A8 B8 C8 D8 六、申請專利範園 5. 如申請專利範圍第1或4項之口服用水膠體徐放性酱 藥錠劑，其中高分子物質爲聚乙嫌氧化物。 6. 如申請專利範圍第1或3項之口服用水膠體徐放性醫 藥錠劑，係由至少⑴製劑全體之8 0重量％以下之一種 以上藥物，0製劑全體之60重量％之親水性基劑’ 及⑶製劑全體之15~90重量％之高分子物質而成。 7. 如申請專利範圍第1或6項之口服用水膨體徐放性醫 藥錠劑，係口服用而其中藥物爲鹽酸尼卡地平 (nicardipine)。 ♦· —.1 i^i n n — ：- - I I I 私 -I - I - .—I— I I. (請先s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 >紙張尺度逋用中國國家搞準(CNS)A4«^-( 210X297^t )Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. Patent Application No. 8210 * 75 No. 72 "Oral Water Colloid Xufang Pharmaceutical Tablets" (Amended on February 25, 89) Six. Patent Application Scope: 1. An oral hydrocolloid radioactive medicinal lozenge is composed of at least 8% by weight or less of the whole tincture preparation, and 5 to S0% by weight of the whole tincture preparation—one or two kinds having a base for dissolving 1 gram of the base agent. The solubility required for the amount of water below 4rol is selected from the group consisting of polyethylene glycol, polyvinylpyrrolidone, D-anhydrol, xylitol, white sugar, anhydrous maltose, D-fructose, polyglucose, glucomannan, Polyoxyethylene hardened castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene anthosaccharide high fatty acid ester, sodium chloride, magnesium chloride, citric acid, tartaric acid, glycine, / 5 · alanine, hydrochloric acid lysine , One or two or more hydrophilic bases of meglumine, and one or two of the weight percent average molecular weight of the whole preparation of more than 2 million, or the viscosity of a 1% aqueous solution (25 ° C) of more than 100,000 cps Macromolecular substances of the above: poly A pharmaceutical composition composed of ethylene oxide, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and hydroxyethyl cellulose 'carboxyvinyl polymer is uniformly mixed to form a tablet. 2. For example, the oral hydrocolloid slow-release medicinal tablet in the scope of patent application, wherein the hydrophilic base is polyethylene glycol or sugar. 3. For example, the oral hydrocolloid slow-release medicinal tablet in the scope of patent application, wherein the hydrophilic base is polyethylene glycol. 4. For example, the oral hydrocolloid radioactive medicinal tablet in the scope of patent application, wherein the polymer substance contains at least one polyethylene oxide. This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) # 0 ^^ 1 1 ^ — — ^ 1 ^^ 1 1 ^ 1 m ^^ 1 —II I ^ nn IH ^^ 1 ^ ^ 1 ..:-. ¾- i (please read the note f on the back first and then write this page) A8 B8 C8 D8 VI. Apply for a patent garden 5. If you apply for the oral hydrocolloid of item 1 or 4 Xufang soy sauce lozenges, of which the polymer substance is polyethylene oxide. 6. For example, the oral water colloidal Xufang lozenge medicine lozenges for patent application item 1 or 3 are made up of at least 80% of the whole preparation. One or more drugs with a content of less than 0% by weight, 60% by weight of a hydrophilic base of the entire formulation, and 15-90% by weight of a high-molecular substance of the entire formulation. Bulking and exfoliating medicinal tablets for oral use are for oral use and the drug is nicardipine hydrochloride. ♦ · —.1 i ^ inn — ：--III Private-I-I-.-I- I I. (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 > Paper Standards Use China National Standards (CNS) A4 «^-(210X297 ^ t)
TW82107572A 1992-09-18 1993-09-15 An oral hydrogel control release pharmaceutical tablet TW393320B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3100720A1 (en) 2015-06-05 2016-12-07 ANXO Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3100720A1 (en) 2015-06-05 2016-12-07 ANXO Pharmaceutical Co., Ltd. Sustained release pharmaceutical composition and preparation method thereof

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